Development and validation of a new radiographic scoring system to evaluate bone and cartilage destruction and healing of large joints with rheumatoid arthritis: ARASHI (Assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging) study.
To assess the reliability and sensitivity of a novel scoring method to evaluate the radiographic appearance of and longitudinal changes including joint remodeling in large joints with early and established rheumatoid arthritis (RA). The ARASHI study group devised new radiographic scoring systems (Status score; range 0-16 points, and Change score; range -11 to 12 points) for evaluation of large joints with RA. Radiographs showing anterior/posterior views of large joints (shoulder, elbow, hip, knee, and ankle joints) taken at two time points (mean interval 2.3 years) were collected from 25 patients with established RA (5 patients for each of the 5 joints, 50 films in total), and an additional 5 films of each joint with severe joint destruction were collected from 5 different sets of RA patients. After consensus on the definition of each component and reader training, images were evaluated using the Larsen's grading system and the ARASHI Status and Change score by 9 independent senior orthopedic surgeons. The reliability was estimated by intra-class correlation coefficients (ICCs) and measurement error by 95% confidence intervals of minimum detectable change (MDC95). ARASHI Status score and Change score significantly correlated with Larsen's grade (r = 0.89, P < 0.0001) and follow-up-baseline differences in Larsen's grade (r = 0.83, P < 0.0001), respectively. Inter-reader ICCs were very high for both Status score (0.88, 95% confidence interval [CI], 0.83-0.92, P < 0.001) and Change score (0.92, 95% CI, 0.87-0.96, P < 0.001). Intra-reader ICCs were also very high for both Status score (0.92, 95% CI, 0.71-0.98, P < 0.001) and Change score (0.97, 95% CI, 0.91-0.99, P < 0.001). The MDC95 for inter-reader agreement were 4.18 (25% of maximum obtainable score, MOS) and 4.99 (21% of MOS) for Status score and Change score, respectively. The MDC95 for intra-reader agreement was acceptable with 2.82 (17% of MOS) and 3.02 (13% of MOS) for Status score and Change score, respectively. The ARASHI scoring method showed good inter-/intra-reader reliability with high ICCs and acceptable MDC95 with respect to each large joint and the components of both Status and Change scores. The results suggest that the ARASHI scoring method might be useful for the assessment of status, as well as longitudinal monitoring of destruction and remodeling of large joints with RA.


Emphysematous sloughed floating ball after prostate water vaporization Rezum: A case report.
Rezūm™ water vapor therapy is a new minimally invasive endoscopic technology for the management and treatment of benign prostatic hyperplasia. A 63-year-old male presented to our department with severe dysuria, frequency, urgency, and interrupted stream 2 mo after receiving Rezūm™ therapy. The symptoms were caused by a retained floating emphysematous necrotic sloughed tissue. We also discovered a persistent bacterial infection that was resistant to parenteral antimicrobial therapy. The treatment of the patient included surgical removal of the necrotic tissue. Despite the good safety profile and minimal adverse events related to Rezūm™ therapy, major complications can still occur.


The complex trans-[RuCl([15]aneN4NO]2+ induces rat aorta relaxation by ultraviolet light irradiation.
The aim of the present study was to investigate the possible endogenous storage of photosensitive nitric oxide, and also to examine the relaxant effect of NO released from the compound by UV light irradiation. Aorta was isolated from rats and the endothelium was mechanically removed. Denuded aortic rings pre-contracted with prostaglandin F(2alpha) responded with relaxation to UV light irradiation. The first stimulation produced the greatest response that decreased until complete disappearance. After this, the addition of the compound in the absence of light did not produce any response. However, in the presence of UV light irradiation, the complex trans-[RuCl([15]aneN4)NO]2+ induced 100% relaxation. After incubation with the nitric oxide scavenger, oxyhaemoglobin, this relaxation was completely abolished. In PGF2(2alpha)-pre-contracted aortas, the time to reach maximum relaxation was only 50s. Taken together, these results suggest that preformed endogenous nitric oxide stores exist in the denuded rat aorta, and that they are sensitive to UV light. The photo-induction of the complex trans-[RuCl([15]aneN4NO]2+ induces complete aorta relaxation, which is due to release of nitric oxide in the extracellular medium.


Bilirubin/albumin ratios in fetal blood and in amniotic fluid in rhesus immunization.
To test the hypothesis that unconjugated bilirubin is equally distributed over the albumin molecules present in fetal blood and amniotic fluid in Rhesus (Rh) immunization. Molar concentrations of unconjugated bilirubin and albumin were measured in fetal blood and amniotic fluid samples, obtained before the first intrauterine transfusion in 30 nonhydropic, anti-D-alloimmunized fetuses, with gestational ages ranging from 20 to 35 weeks. Bilirubin concentration in amniotic fluid was best predicted by a combination of bilirubin concentration in fetal blood (P<.001), albumin concentration in fetal blood (P=.008), and albumin concentration in amniotic fluid (P<.001) (adjusted R2=0.91). The bilirubin/albumin ratios in fetal blood were linearly correlated with the bilirubin/albumin ratios in amniotic fluid (R2=0.75, P<.001). However, the bilirubin/albumin ratios in fetal blood were always higher than the bilirubin/albumin ratios in amniotic fluid (regression coefficient 1.4, 95% confidence interval 1.1-1.7). In our population, a bilirubin/albumin ratio in amniotic fluid of 0.10 or greater had a better sensitivity and specificity to predict severe anemia (Z hemoglobin -5 standard deviations or less) than the Queenan 4 or the Liley 2c line. The relation between fetal hemolysis and amniotic fluid bilirubin concentration is based on the linear correlation between bilirubin/albumin ratios in fetal blood and in amniotic fluid. The slope in Queenan's and Liley's chart follows that of the albumin concentration in amniotic fluid during gestation. III.


Involvement of human herpesvirus-6 variant B in classic Hodgkin's lymphoma via DR7 oncoprotein.
Hodgkin's lymphoma (HL) is associated with the presence of EBV in Reed-Sternberg (RS) cells in ∼40% of cases. Here, we studied the presence of human herpesvirus type 6 (HHV-6) variant B in RS cells of HL patients and correlated results with clinical parameters. We then examined the implication of HHV-6 DR7B protein in cell deregulation. HHV-6 DR7B protein was produced in a Semliki Forest virus system. Polyclonal antibodies were then generated and used for immunochemical HHV-6 localization in HL biopsies. Binding between DR7B and p53 was studied using a double-hybrid system. Transactivation of NFκB was observed after transient transfection using reporter gene assays. We looked for Id2 factor expression after stable transfection of the BJAB cell line by reverse transcription-PCR and Western blot analysis. HHV-6 was more common in nodular sclerosis subtype HL, and DR7B oncoprotein was detected in RS cells for 73.7% of EBV-negative patients. Colocalization of EBV and HHV-6 was observed in RS cells of doubly infected patients. DR7B protein bound to human p53 protein. p105-p50/p65 mRNA expression and activation of the NFκB complex were increased when DR7B was expressed. Stable expression of DR7B exhibited a strong and uniform expression of Id2. A slightly higher percentage of remission was observed in patients with RS cells testing positive for DR7B than in those testing negative. Collectively, these data provide evidence for the implication of a novel agent, HHV-6, in cases of nodular sclerosis HL.


Orbitally shaken single-use bioreactors.
: Orbitally shaken single-use reactors are promising reactors for upstream processing, because they fulfill three general requirements for single-use equipment. First, the design of the disposable parts is inherently simple and cost-efficient, because no complex built-in elements such as baffles or rotating stirrers are required. Second, the liquid distribution induced by orbital shaking is well-defined and accurately predictable. Third, the scale-up from small-scale systems, where shaken bioreactors are commonly applied, is simple and has been successfully proven up to the cubic meter scale. However, orbitally shaken single-use reactors are only suitable for certain applications such as cultivating animal or plant cells with low oxygen demand. Thus, detailed knowledge about the performance of such systems on different scales is essential to exploit their full potential. This article presents an overview about opportunities and limitations of shaken single-use reactors.


The children's apperception test evaluation form: initial data.
Some indexes and variables of the Children's Apperception Test Evaluation Form were used to evaluate children's thematic apperception stories to Bellak's test. The protocols were scored for four indexes: (1) number of words, (2) number of characters (animals) rightly identified, (3) number of modified characters (animals), (4) number of attributions given to the characters (animals) in the stories. The form was also scored for number and types of conflicts evoked in children. Interscorer relilability coefficients were high for all the indexes and variables. The sample included 70 children ages 4.5 to 11.5 yr. The relationship between scores and age and sex was also investigated.


RHEMITT Score: Predicting the Risk of Rebleeding for Patients with Mid-Gastrointestinal Bleeding Submitted to Small Bowel Capsule Endoscopy.
Small bowel capsule endoscopy (SBCE) is the gold standard for mid-gastrointestinal bleeding (MGIB). No score has been developed to predict the risk of small bowel rebleeding after SBCE. Creating a predictive small bowel rebleeding risk score for MGIB, after initial SBCE. Retrospective, single center study, including SBCEs for MGIB, from June 2006 to October 2016. The minimum follow-up was 12 months. Univariate analysis and a multivariable Cox regression model tested the association with rebleeding. Statistically significant variables were used to compute the score. The score's accuracy was tested through a receiver operating characteristic (ROC) curve. A classification tree identified risk groups. For internal validation, we performed a 5-fold cross validation. We assessed 357 SBCEs for MGIB, of which 88 (24.6%) presented rebleeding during follow-up. Seven variables were used to compute a risk-predicting score - the RHEMITT score - namely, renal disease; heart failure; endoscopic capsule P1/P2 lesions; major bleeding; incomplete capsule; tobacco consumption; and endoscopic treatment. The score presented good accuracy toward the outcome (area under the curve ROC 0.842, 95% CI 0.757-0.927). We established 3 rebleeding risk groups: low (0-3 points); intermediate (4-10 points); and high (+11 points). A new MGIB score, named RHEMITT, accurately anticipates the individual risk of small bowel rebleeding after initial SBCE.


Magnetic Resonance Imaging of Total Ankle Arthroplasty: State-of-The-Art Assessment of Implant-Related Pain and Dysfunction.
Total ankle arthroplasty (TAA) is an effective alternative for treating patients with end-stage ankle degeneration, improving mobility, and providing pain relief. Implant survivorship is constantly improving; however, complications occur. Many causes of pain and dysfunction after total ankle arthroplasty can be diagnosed accurately with clinical examination, laboratory, radiography, and computer tomography. However, when there are no or inconclusive imaging findings, magnetic resonance imaging (MRI) is highly accurate in identifying and characterizing bone resorption, osteolysis, infection, osseous stress reactions, nondisplaced fractures, polyethylene damage, nerve injuries and neuropathies, as well as tendon and ligament tears. Multiple vendors offer effective, clinically available MRI techniques for metal artifact reduction MRI of total ankle arthroplasty. This article reviews the MRI appearances of common TAA implant systems, clinically available techniques and protocols for metal artifact reduction MRI of TAA implants, and the MRI appearances of a broad spectrum of TAA-related complications.


Nutritional Status Is Associated With Clinical Progression in Alzheimer's Disease: The NUDAD Project.
In cognitively normal adults, nutritional parameters are related to cognitive decline and incidence of dementia. Studies on the role of nutrition in predementia stages subjective cognitive decline and mild cognitive impairment, and mild stages of Alzheimer's disease (AD) dementia in a clinical setting are lacking. In the absence of a curative treatment, this evidence is important for targeting nutritional factors to potentially prevent or delay further cognitive decline. Our aim is to investigate associations of nutritional parameters with clinical progression in patients ranging from those who are cognitively normal to those who have AD dementia. Longitudinal. Memory clinic, 551 patients (219 with subjective cognitive decline, 135 with mild cognitive impairment, and 197 with AD dementia), mean age 64 ± 8 years. We assessed body mass index, fat-free mass, Mini-Nutritional Assessment, and dietary intake with the Dutch Healthy Diet food frequency questionnaire and the 238-item healthy life in an urban setting (HELIUS) food frequency questionnaire at baseline. Cox proportional hazard models were used to evaluate associations of nutritional parameters with clinical progression. Additional analyses were restricted to patients who were amyloid positive. We observed clinical progression in 170 patients (31%) over 2.2 ± 0.9 years. Poorer Mini-Nutritional Assessment score [hazard ratio (95% confidence interval) 1.39 (1.18-1.64)], lower body mass index [1.15 (0.96-1.38)], lower fat-free mass [1.40 (0.93-2.10)], and a less healthy dietary pattern [1.22 (1.01-1.48)] were associated with a higher risk of clinical progression. Similar effect sizes were found in patients who were amyloid positive. Poorer nutritional status and a less healthy dietary pattern are associated with a higher risk of clinical progression. This study provides support for investigating whether improving nutritional status can alter the clinical trajectory of AD.


The regulation of insulin and glucagon secretion by opiates: a study with naloxone in healthy humans.
The presence of beta-endorphin and enkephalin in pancreatic islets suggests that opioid peptides may play a role in the regulation of pancreatic endocrine function. Since data in the literature are rather controversial, we examined the effects of different doses of naloxone on insulin and glucagon secretion in 21 healthy nonobese volunteers (6 women and 15 men) by measuring the variations of insulin and glucagon plasma levels following a 5-g i.v. glucose load before and during a 30-min naloxone infusion. Total amounts of 0.4 and 0.8 mg of naloxone failed to modify serum insulin and plasma glucose responses to glucose challenge. On the contrary, 0.2 mg/kg (i.e. 12-14 mg per subject as total amount) given to 3 women and 6 men led to a glucose-induced insulin release significantly lower than that recorded in basal conditions, with corresponding greater plasma glucose elevation. The suppressive effect of glucose on glucagon concentration was less pronounced during naloxone. Data reported here suggests that inhibition of opiate receptors in human pancreas occurs only with large amounts of naloxone. Moreover, they may indirectly support the stimulatory role of opioid peptides on insulin secretion in man, according to some experimental in vitro and in vivo studies. In addition, naloxone seems to reduce pancreatic A-cell sensitivity to hyperglycemia.


Commitment to division in Paramecium: effect of nutrient level on the macronuclear DNA increment.
In Paramecium, a fixed macronuclear DNA increment is associated with commitment to cell division. This study shows that this threshold DNA increment is about 70% of the final DNA increment in well-fed cells. The DNA increment is reduced when growth rate is decreased and decreases in parallel with growth rate to a minimum of 30% of the normal DNA increment. This minimum value is obtained when the growth rate is 20% of its normal level or lower. Further reduction in the growth rate produces no further reduction in the DNA increment. Following abrupt nutrient-level shifts, both the threshold DNA increment and the final DNA increment change progressively as the time of the shift is moved to later stages of the cell cycle. The threshold DNA increment is reset following nutrient-level shifts up to the point of commitment to division. These observations are consistent with the notion that the magnitude of the threshold DNA increment is strongly correlated with the rate of growth and is rapidly reset by factors which alter the growth rate. The implications of these observations for growth-driven regulation of the cell cycle are discussed.


Benzimidazole clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: new anticancer agents.
Two series of Benzimidazole clubbed with triazolo-thiadiazoles (5a-q, 5r, 5s and 5x-a(1)) and triazolo-thiadiazines (5t-w) were synthesized with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were investigated at the National Cancer Institute (NCI) against NCI 60 cell line panel; results showed good to remarkable broad-spectrum anticancer activity. Among them, the compound 5h (NCS: 760452, 1-(1H-benzo [d] imidazol-2-yl)-3-(6-(2,4-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl) propan-1-one) exhibited significant growth inhibition with GI50 values ranging from 0.20 to 2.58 μM and found superior selectivity for the leukemia cell lines and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). The 5h may possibly be used as lead compound for developing new anticancer agents.


Treatment effects of phosphorylated Chrysanthemum indicum polysaccharides on duck viral hepatitis by protecting mitochondrial function from oxidative damage.
To define the underlying mechanism of the beneficial role of Chrysanthemum indicum polysaccharides (CIPS) and phosphorylated Chrysanthemum indicum polysaccharides (pCIPS) in duck viral hepatitis (DVH), we evaluated the protective effects of the CIPS and pCIPS against DVH in terms of antioxidation and mitochondrial function. Fluorescence probes and several assay kits were used to determine the oxidative stress and mitochondrial dysfunction in vitro and vivo. Additionally, transmission electron microscopy was applied to observe the changes of mitochondrial ultrastructure in the liver tissue. Our results indicate that the CIPS and pCIPS significantly enhanced the survival of duck hepatitis A virus type 1 (DHAV-1) infected ducklings. Moreover, the CIPS and pCIPS suppressed oxidative stress and preserved mitochondrial function, such as enhanced antioxidant enzyme activity, increased ATP production, and stabilized mitochondrial membrane potential (MMP). Meanwhile, the results of hematoxylin-eosin (HE) staining and serum biochemical examination demonstrated that treatment with the CIPS and pCIPS could decrease focal necrosis and infiltration of inflammatory cells, which in turn reducing liver injury. Furthermore, the CIPS and pCIPS were able to preserve liver mitochondrial membrane integrity in DHAV-1 challenged ducklings. Notably, the pCIPS was significantly outperformed the CIPS on all measures of liver and mitochondrial function. These results suggested that mitochondrial homeostasis plays an important role in alleviating oxidative damage in the livers, and the hepatocyte protective effects of the CIPS were enhanced after phosphorylation modification.


Women's perceptions of their healthcare experience when they choose not to breastfeed.
How do women who choose not to breastfeed perceive their healthcare experience? This qualitative research study used a phenomenographic approach to explore the healthcare experience of women who do not breastfeed. Seven women were interviewed about their healthcare experience relating to their choice of feeding, approximately 4 weeks after giving birth. Six conceptions were identified and an outcome space was developed to demonstrate the relationships and meaning of the conceptions in a visual format. There were five unmet needs identified by the participants during this study. These needs included equity, self sufficiency, support, education and the need not to feel pressured. Women in this study who chose not to breastfeed identified important areas where they felt that their needs were not met. In keeping with the Code of Ethics for Nurses and Midwives, the identified needs of women who do not breastfeed must be addressed in a caring, compassionate and just manner. The care and education of women who formula feed should be of the highest standard possible, even if the choice not to breastfeed is not the preferred choice of healthcare professionals.


Cervical artery dissection following a turbulent flight.
Cervical artery dissection is a common cause of stroke in young patients without vascular risk factors and may affect the carotid or vertebral arteries. The risk of spontaneous dissection is higher in those with genetic predisposing factors while other cases may be precipitated by an event involving head or neck movement or associated with direct neck trauma. We present the case of a previously well young woman with a history of migraine who developed internal carotid artery dissection following a turbulent short-haul commercial flight while restrained using a seatbelt. We propose that repetitive flexion-hyperextension neck movements encountered during the flight were the most likely precipitant of carotid artery dissection in this case and review the therapeutic options available.


The effect of methylglyoxal-bis(guanylhydrazone) on mitochondrial Ca(2+) fluxes.
Methylglyoxal-bis(guanylhydrazone) (MGBG) induces a dose-dependent inhibition of the electrophoretic Ca(2+) uptake by rat liver mitochondria (RLM) without affecting the electrical membrane potential. MGBG is also able to inhibit the electroneutral Ca(2+) release from mitochondria. These effects result in a progressive increase of Ca(2+) level in suspending medium indicating that Ca(2+) uptake is inhibited at higher extent than Ca(2+) efflux. Spermine instead, induces a lowering of external Ca(2+) concentration. This action is reversed by MGBG which again raises the external Ca(2+) concentration then in the absence of spermine, though at a lower extent. The mechanism of MGBG effects and their implications on energy metabolism are discussed.


Amniotic fluid embolism rescued by venoarterial extracorporeal membrane oxygenation.
Amniotic fluid embolism (AFE) is a rare but often catastrophic complication of pregnancy that leads to cardiopulmonary dysfunction and severe disseminated intravascular coagulopathy (DIC). Although few case reports have reported successful use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) with AFE, concerns can be raised about the increased bleeding risks with that device. This study included patients with AFE rescued by VA-ECMO hospitalized in two high ECMO volume centers between August 2008 and February 2021. Clinical characteristics, critical care management, in-intensive care unit (ICU) complications, and hospital outcomes were collected. ICU survivors were assessed for health-related quality of life (HRQL) in May 2021. During that 13-year study period, VA-ECMO was initiated in 54 parturient women in two high ECMO volume centers. Among that population, 10 patients with AFE [median (range) age 33 (24-40), SAPS II at 69 (56-81)] who fulfilled our diagnosis criteria were treated with VA-ECMO. Pregnancy evolved for 36 (30-41) weeks. Seven patients had a cardiac arrest before ECMO and two were cannulated under cardiopulmonary resuscitation. Pre-ECMO hemodynamic was severely impaired with an inotrope score at 370 (55-1530) μg/kg/min, a severe left ventricular ejection fraction measured at 14 (0-40)%, and lactate at 12 (2-30) mmol/L. 70% of these patients were alive at hospital discharge despite an extreme pre-ECMO severity and massive blood product transfusion. However, HRQL was lower than age-matched controls and still profoundly impaired in the role-physical, bodily pain, and general health components after a median of 44 months follow-up. In this rare per-delivery complication, our results support the use of VA-ECMO despite intense DIC and ongoing bleeding. Future studies should focus on customized, patient-centered, rehabilitation programs that could lead to improved HRQL in this population.


Attenuation of cell cycle regulator p27(Kip1) expression in vertebrate epithelial cells mediated by extracellular signals in vivo and in vitro.
Cell cycle arrest in potentially dividing cells is often mediated by inhibitors of G1/S-phase cyclin-dependent kinases. The cyclin E/CDK2-inhibitor p27(Kip1) has been implicated in this context in epithelial cells. We cloned and sequenced p27(Kip1) of ducklings (Anas platyrhynchos) and used an in vitro assay system to study the mechanism of p27(Kip1) downregulation in the nasal gland which precedes an increase in proliferation rate upon initial exposure of the animals to osmotic stress. Western blot studies revealed that p27(Kip1) is downregulated during 24 h of osmotic stress in ducklings with the steepest decline in protein levels between 5 and 8 h. As indicated by the results of Northern blot and semi-quantitative PCR studies, protein downregulation is not accompanied by similar changes in mRNA levels indicating that Kip1 is regulated mainly at the translational (synthesis) or posttranslational level (degradation). Using recombinant duck Kip1 protein expressed in E. coli, we showed that Kip1 is subject to polyubiquitinylation by cytosolic enzymes from nasal gland cells indicating that loss of Kip1 may be regulated, at least in part, by acceleration of protein degradation. In cultured nasal gland tissue, attenuation of Kip1 expression could be induced by activation of the muscarinic acetylcholine receptor indicating that mAChR-receptor signalling may play a role in the re-entry of quiescent gland cells into the cell cycle.


Migration inhibition of lymph node lymphocytes as an in vitro assay for cell-mediated immunity in the draining lymph nodes of parenterally immunized mice.
This paper describes a method for in vitro measurement of specific cell-mediated immunity in the mouse. Animals were immunized parenterally with ovalbumin in Freund's incomplete or complete adjuvant, and a direct migration inhibition assay was performed, using lymphoid cells from the draining lymph nodes. Migration inhibition was found to be antigen specific, correlated with systemic delayed-type hypersensitivity measured in vivo by skin testing, and had a high degree of sensitivity for ovalbumin. The migrating cells were identified as lymphocytes. Lymph node lymphocyte migration inhibition provides a reliable in vitro assay for regional CMI in the mouse.


Pancreatitis with panniculitis and arthritis: a rare association.
A case of pancreatitis with polyarthritis and panniculitis is reported because of its rarity and the severe nature of the disease.


From phone use to speeding and driving under influence: Identifying clusters of driving risk behaviors as an opportunity for targeted interventions.
Identifying the profile of risky behaviors among drivers is central to propose effective interventions. Due to the multidimensional and overlapping aspects of risky driving behaviors, cluster analysis can provide additional insights in order to identify specific subgroups of risk. This study aimed to identify clusters of driving risk behavior (DRB) among car drivers, and to verify intra-cluster differences concerning clinical and sociodemographic variables. We approached a total of 12,231 drivers and we included 6392 car drivers. A cluster algorithm was used to identify groups of car drivers in relation to the DRB: driving without a seat belt (SB), exceeding the speed limit (SPD), using a cell phone while driving (CELL), and driving after drinking alcohol (DUI). The algorithm classified drivers within five different DRB profiles. In cluster 1 (20.1%), subjects with a history of CELL. In cluster 2 (41.4%), drivers presented no DRB. In cluster 3 (9.3%), all drivers presented SPD. In cluster 4 (12.5%), drivers presented all DRB. In cluster 5 (16.6%), all drivers presented DUI. Clusters with DUI-related offenses (4 and 5) comprised more men (81.9 and 78.8%, respectively) than the overall sample (63.4%), with more binge drinking (50.9 and 45.7%) and drug use in the previous year (13.5 and 8.6%). Cluster 1 had a high years of education (14.4 ± 3.4) and the highest personal income (Md = 3000 IQR [2000-5000]). Cluster 2 had older drivers (46.6 ± 15), and fewer bingers (10.9%). Cluster 4 had the youngest drivers (34.4 ± 11.4) of all groups. Besides reinforcing previous literature data, our study identified five unprecedented clusters with different profiles of drivers regarding DRB. We identified an original and heterogeneous group of drivers with only CELL misuse, as well as other significant differences among clusters. Hence, our findings show that targeted interventions must be developed for each subgroup in order to effectively produce safe behavior in traffic.


[Significance of beta-adrenoreception in realizing the glycogenolytic and lipolytic effects of excess thyroid hormones].
In experiments on rats the chronic administration of beta-adrenoblocker obsidan (propranolol) in doses blocking the glycogenolytic and lipolytic effects of exogenous epinephrine does not prevent a decrease in the liver and heart glycogen level and an increase of free fatty acids (FFA) in the serum as well as of lipolytic activity of adipose tissue in vitro, which are produced by high doses of thyroxine.


Carmofur-induced organic mental disorders.
Organic mental disorder was observed in a 29-year-old female in the prognostic period after the onset of carmofur-induced leukoencephalopathy. Symptoms such as euphoria, emotional lability and puerile attitude noted in the patient were diagnosed as organic personality syndrome according to the criteria defined in the DSM-III-R. It is referred to as a frontal lobe syndrome. Brain CT revealed a periventricular low density area in the frontal white matter and moderate dilatation of the lateral ventricles especially at the bilateral anterior horns. Consequently, carmofur-induced leukoencephalopathy may uncommonly result in organic personality syndrome in the residual state. It may be attributed to the structural damage to the frontal lobe.


The accuracy of antenatal ultrasound in the detection of facial clefts in a low-risk screening population.
To evaluate the accuracy of prenatal ultrasound in the detection of facial clefts in a low-risk screening population and to report on the outcome of these pregnancies. We retrospectively reviewed antenatal ultrasound records from the obstetric ultrasound department, postnatal records from the regional craniofacial unit and autopsy reports of fetuses over 16 weeks' gestational age from the regional pathology department over a 5-year period (1993-97). Cross-referencing between the three data sets identified all cases of facial clefts. Out of 23 577 live and still births, 30 had facial clefts; four were excluded from the study. Of the remaining 26 cases, 10 had associated major anomalies. There were 19 live births and seven terminations. Six of the seven terminations had other major abnormalities. Our detection rate for cleft lip and palate was 93% and the detection rate for isolated cleft palate was 22%. Isolated cleft lip was detected in 67% of cases. The overall detection rate for facial clefts was 65%. From our results and a review of the literature it is clear that before standards can be set we need to define which facial clefts are sonographically demonstrable. Our data provide information for effective counseling and setting of standards for clinical practice.


Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: associations with organ manifestations, immunolaboratory markers and disease activity indices.
Some tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis. We assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement. TAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively. There were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6+/-1.7 vs 1.8+/-1.4 mg/l) and CA15-3 (22.9 +/- 1.8 vs 18.6 +/- 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls. The concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.


The Value of Macrolide-Based Regimens for Community-Acquired Pneumonia.
Macrolide antimicrobials are commonly prescribed, specifically for the treatment of respiratory tract infections. Although still effective, the development of widespread macrolide resistance has limited their use. Aside from their antimicrobial effects, macrolides are also known to possess immune-modulatory properties which may confer a survival benefit in both acute and chronic inflammatory states. This review discusses the efficacy, potential mechanisms, and adverse effects of macrolide therapy specifically in community-acquired pneumonia in outpatients, hospitalized ward patients, and those requiring intensive care unit admission. Challenges for ongoing research in this field are discussed and treatment recommendations offered.


[Metastatic Crohn disease of the scrotum].
We report herein a rare case of metastatic Crohn's disease involving the penile and scrotal skin in a 56-year old man. We review the literature about this rare entity and describe its clinicopathological characteristics.


The emerging role of complement in neuromuscular disorders.
The complement cascade is a key arm of the immune system that protects the host from exogenous and endogenous toxic stimuli through its ability to potently regulate inflammation, phagocytosis, and cell lysis. Due to recent clinical trial successes and drug approvals for complement inhibitors, there is a resurgence in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several diseases. In particular, neuromuscular diseases are undergoing a recent focus, with demonstrated links between complement activation and disease pathology. This review aims to provide a comprehensive overview of complement activation and its role during the initiation and progression of neuromuscular disorders including myasthenia gravis, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. We will review the preclinical and clinical evidence for complement in these diseases, with an emphasis on the complement-targeting drugs in clinical trials for these indications.


Common neurologic syndromes in medical practice.
The cases presented here are intended to illustrate an approach to the patient with complaints which may be vague, evanescent, or related to emotional factors. A scheme to analyze only five factors, mood, movement, sensation, cognition, and consciousness is presented to simplify the complexity of human behavior in order to arrive at correct diagnoses. The importance of a complete medical evaluation is stressed. Psychosis and other major psychiatric illness have been alluded to, but space does not permit discussion of the very important issues of the genetics, the neurochemistry, and the differential diagnosis of schizophrenia, mood disorders, and the organic brain syndromes. Some of the many manifestations of epilepsy have been presented, and the importance of electroencephalography and computed axial tomography is stressed. The references have been chosen for their general utility to practicing clinicians, especially the works of Pincus, Glaser and Tumulty.


Short-run tests for determining harmful effects of PCB-containing engine oils on cells.
Our main objective was to set up reproducible methods for a rapid determination of harmful effects of PCB-containing engine oils on cells. We used a plate method and Scenedesmus quadricauda, Saccharomyces cerevisiae, Rhodotorula glutinis and Pseudomonas putida as test organisms.


Initiation of smooth-pursuit eye movements by real and illusory contours.
It is well established that elementary motion detectors are only able to code for the movement of a contour perpendicular to its orientation. This shortcoming explains why the initial direction of smooth-pursuit eye movements is directed orthogonal to the orientation of a moving contour independent of its veridical direction of motion. Here, we replicated this finding and asked whether this directional error can be reduced by subjects' prediction of upcoming target moving direction and whether this directional error also occurs during tracking of an illusory contour. Our results show that prediction did not abolish the directional error, it was only slightly reduced. On the other hand, the directional error was considerably diminished during pursuit initiation towards illusory contours and most likely reflected the amount of real stimulation defining the specific illusory contour. We conclude that pursuit initiation is driven by raw retinal image motion signals, which are not yet processed for figure completion.


Electrogeneration of H(2) for Pd-catalytic hydrodechlorination of 2,4-dichlorophenol in groundwater.
A novel electrolytic groundwater remediation process, which used the H(2) continuously generated at cathode to achieve in situ catalytic hydrodechlorination, was developed for the treatment of 2,4-dichlorophenol (2,4-DCP) in groundwater. Catalytic hydrodechlorination using Pd supported on bamboo charcoal and external H(2) showed that 2,4-DCP was completely dechlorinated to phenol within 30 min at pH ≤ 5.5. In a divided electrolytic system, the catalytic hydrodechlorination of 2,4-DCP in cathodic compartment by H(2) generated at the cathode under 20 and 50 mA reached 100% at 120 and 60 min, respectively. Two column experiments with influent pHs of 5.5 (unconditioned) and 2 were conducted to evaluate the feasibility of this process. The 2,4-DCP removal efficiencies were about 63% and nearly 100% at influent pHs of 5.5 and 2, respectively. Phenol was solely produced by 2,4-DCP hydrodechlorination, and was subsequently degraded at the anode. A low pH could enhance the hydrodechlorination, but was not necessarily required. This study provides the preliminary results of a novel effective electrolytic process for the remediation of groundwater contaminated by chlorinated aromatics.


Septin1, a new interaction partner for human serine/threonine kinase aurora-B.
Several families of kinases work together to ensure the rate and precision of mitosis. Aurora-B is an important serine/threonine kinase required for chromosome segregation and cytokinesis. Identification of Aurora-B substrates will help to enhance our understanding of the molecular mechanism of mitosis. Through a yeast two-hybrid screen, we found a novel partner of Aurora-B, Septin1, belonging to a conserved family of GTPase proteins that localize to the cleavage furrow and are involved in cytokinesis. We confirmed this interaction using Co-immunoprecipitation experiments in mammalian cells and GST-pull-down analysis in vitro. Moreover, Aurora-B can phosphorylate Septin1 in vitro. We identified that Ser248, Ser307, and Ser315 are the main phosphorylation sites in Septin1. These two proteins partially co-localize to the midbody during cytokinesis. So, it is possible that Septin1's role in the regulation of cytokinesis is related to its phosphorylation by Aurora-B. Unlike previous reports that Septins function in cytokinesis and localize to the cleavage furrow, we found that Septin1 localizes to the spindle pole throughout mitosis, indicating that Septin1 may function in chromosome segregation as well.


Novel JAK2 Exon 14 Mutations L611S or N622Y in cis with JAK2V617F Are Associated with Distinct Clinical Phenotype of Polycythemia Vera and Concurrent Eosinophilia.
Eosinophilic phenotypes in polycythemia vera (PV) and essential thrombocythemia (ET) are rare and poorly characterized. Co-occurring JAK2 mutations in cis, specifically L611S or N622Y mutations, appear to result in a more aggressive clinical phenotype. PV/ET with eosinophilic phenotypes may require full next-generation sequencing to capture co-occurring mutations as opposed to more prevalent single-gene assays. These eosinophilic phenotypes are highly thrombotic and systemic symptoms appear responsive to early use of the janus kinase inhibitor ruxolitinib.


Isolation, characterization and molecular docking of novel umami and umami-enhancing peptides from Ruditapes philippinarum.
To understand the taste of the Ruditapes philippinarum, 14 novel umami peptides were isolated and identified by gel chromatography, HPLC and UPLC-ESI-QTOF-MS/MS. Separations were combined with sensory evaluations and electronic tongue determinations. The peptide sequences were GRVSNCAA, SEEK, KEMQKN, KSAEN, QIEELEGK, TDVEQEGD, HNESQN, RGEPNND, TGDPEK, KGGGGP, TYLPVH, PAATIPE, GPAGPAGPR and AGAGPTP. All peptides had umami and umami-enhancing qualities, KSAEN and QIEELEGK had higher sensory evaluation than the others, while PAATIPE and HNESQN had the best umami-enhancing taste in a 0.35% MSG solution. Molecular docking of the peptides with T1R1/T1R3 indicated that Ser123, Ser146 and Tyr143 may be important in the interaction of the peptides with T1R3. Arg303, Ser123 and Asp166 appear to be involved in the synergistic effect of umami peptides combined with monosodium glutamate. The omission test and the addition test confirmed that the 14 umami peptides contributed to the umami taste of R. philippinarum.


Effect of Bleaching Processes on Physicochemical and Functional Properties of Cellulose and Carboxymethyl Cellulose from Young and Mature Coconut Coir.
The objective of this study was to characterize the properties of cellulose and CMC synthesized from young and mature coconut coir with different bleaching times (bleaching for the first time; 1 BT, bleaching for a second time; 2 BT, and bleaching for the third time; 3 BT) using hydrogen peroxide (H2O2). The surface morphology, structural information, chemical compositions, and crystallinity of both cellulose and CMC were determined. H2O2 bleaching can support delignification by reducing hemicellulose and lignin, as evidenced by FTIR showing a sharp peak at wave number 1260 cm-1. The cellulose and CMC from coconut coir can be more dispersed and have greater functional characteristics with increasing bleaching times due to the change in accessibility of hydroxyl groups in the structure. The CMC diffraction patterns of coconut coir after the bleaching process showed the destruction of the crystalline region of the original cellulose. The SEM images showed that the surface of CMC was smoother than that of cellulose. The CMCy had a higher water holding capacity (WHC) compared to the CMCm as the bleaching can increase interaction between the polymer and water molecules. Therefore, the best quality of CMC corresponds to CMCy. Based on these findings, bleaching time has a strong effect on the functional properties of cellulose and CMC from coconut coir.


Twin-S: a digital twin for skull base surgery.
Digital twins are virtual replicas of real-world objects and processes, and they have potential applications in the field of surgical procedures, such as enhancing situational awareness. We introduce Twin-S, a digital twin framework designed specifically for skull base surgeries. Twin-S is a novel framework that combines high-precision optical tracking and real-time simulation, making it possible to integrate it into image-guided interventions. To guarantee accurate representation, Twin-S employs calibration routines to ensure that the virtual model precisely reflects all real-world processes. Twin-S models and tracks key elements of skull base surgery, including surgical tools, patient anatomy, and surgical cameras. Importantly, Twin-S mirrors real-world drilling and updates the virtual model at frame rate of 28. Our evaluation of Twin-S demonstrates its accuracy, with an average error of 1.39 mm during the drilling process. Our study also highlights the benefits of Twin-S, such as its ability to provide augmented surgical views derived from the continuously updated virtual model, thus offering additional situational awareness to the surgeon. We present Twin-S, a digital twin environment for skull base surgery. Twin-S captures the real-world surgical progresses and updates the virtual model in real time through the use of modern tracking technologies. Future research that integrates vision-based techniques could further increase the accuracy of Twin-S.


Oral magnesium supplementation improves glycaemic status in subjects with prediabetes and hypomagnesaemia: A double-blind placebo-controlled randomized trial.
This study evaluated the efficacy of oral magnesium supplementation in the reduction of plasma glucose levels in adults with prediabetes and hypomagnesaemia. A total of 116 men and non-pregnant women, aged 30 to 65 years with hypomagnesaemia and newly diagnosed with prediabetes, were enrolled into a randomized double-blind placebo-controlled trial to receive either 30 mL of MgCl2 5% solution (equivalent to 382 mg of magnesium) or an inert placebo solution once daily for four months. The primary trial endpoint was the efficacy of magnesium supplementation in reducing plasma glucose levels. At baseline, there were no significant statistical differences in terms of anthropometric and biochemical variables between individuals in the supplement and placebo groups. At the end of follow-up, fasting (86.9 ± 7.9 and 98.3 ± 4.6 mg/dL, respectively; P = 0.004) and post-load glucose (124.7 ± 33.4 and 136.7 ± 23.9 mg/dL, respectively; P = 0.03) levels, HOMA-IR indices (2.85 ± 1.0 and 4.1 ± 2.7, respectively; P = 0.04) and triglycerides (166.4 ± 90.6 and 227.0 ± 89.7, respectively; P = 0.009) were significantly decreased, whereas HDL cholesterol (45.6 ± 10.9 and 46.8 ± 9.2 mg/dL, respectively; P = 0.04) and serum magnesium (1.96 ± 0.27 and 1.60 ± 0.26 mg/dL, respectively; P = 0.005) levels were significantly increased in those taking MgCl2 compared with the controls. A total of 34 (29.4%) people improved their glucose status (50.8% and 7.0% in the magnesium and placebo groups, respectively; P < 0.0005). Our results show that magnesium supplementation reduces plasma glucose levels, and improves the glycaemic status of adults with prediabetes and hypomagnesaemia.


Sexual differentiation of the effects of emotional stress on food intake in rats.
Although gender differences in the response to stress have been reported, differences in stress-induced changes in feeding behavior have not been well studied. In this report, inhibition of food intake was compared in male and female rats following 1 h of restraint, electric footshock, or emotional stress induced by a communication box. Although the three stressors inhibited food intake in both genders, only emotional stress caused a gender difference, a greater inhibition of food intake in female rats (48%) than in male rats (22%). The inhibition of food intake by emotional stress in female rats was more prominent during proestrus than the other phases of estrous cycle. In female rats in proestrus emotional stress showed a greater inhibition of food intake than footshock and restraint. Ovariectomy reduced the inhibition of food intake by emotional stress to the same level as that in male, and replacement with estradiol restored the inhibition to the level of the normal female rats. A corticotropin-releasing factor (CRF) type 1 receptor antagonist prevented emotional stress-induced inhibition of food intake, indicating the involvement of CRF type 1 receptor in emotional stress-induced inhibition of food intake. These results suggest that female rats show a greater inhibition of food intake in response to emotional stress than male rats and that estrogen plays a role in the gender difference.


A quantitative evaluation of the Hewlett-Packard 78354A noninvasive blood pressure meter.
Oscillometrically determined brachial artery pressures were compared with simultaneous contralateral radial intraarterial pressures in 19 anesthetized adult cardiac surgical patients throughout their surgical procedures, interrupted only by nonpulsatile, low-pressure, low-flow cardiopulmonary bypass. Radial intraarterial pressure values ranged widely for systolic (55 to 207 torr), mean (43 to 141 torr), and diastolic (26 to 106 torr). Both error specification methods proposed by the Association for the Advancement of Medical Instrumentation were used and compared. As expected, error method 1 gave consistently lower mean errors, smaller error standard deviations, and higher correlation coefficients than did error method 2. The errors during time periods immediately before and after cardiopulmonary bypass were compared with those from more quiescent times. Higher mean errors, larger error standard deviations, and lower correlation and regression coefficients were found during those time periods surrounding cardiopulmonary bypass. In general, mean errors were lowest for systolic pressure, followed by mean and diastolic pressures in that order, whereas error standard deviations were smallest for mean pressure, followed by systolic and diastolic pressures. Correlation and regression coefficients were highest for systolic pressure, followed by mean and diastolic pressures. In summary, the oscillometric method provides convenient and reproducible estimates of radial intraarterial pressure during most clinical situations, typically with better accuracy than the auscultatory Korotkoff method. The accuracy and reproducibility are diminished during those periods immediately surrounding cardiopulmonary bypass, perhaps due to direct surgical manipulation of the heart with its attendant rapid changes in cardiac output and blood pressure.


Device-quality, reconfigurable metamaterials from shape-directed nanocrystal assembly.
Anchoring nanoscale building blocks, regardless of their shape, into specific arrangements on surfaces presents a significant challenge for the fabrication of next-generation chip-based nanophotonic devices. Current methods to prepare nanocrystal arrays lack the precision, generalizability, and postsynthetic robustness required for the fabrication of device-quality, nanocrystal-based metamaterials [Q. Y. Lin et al. Nano Lett. 15, 4699-4703 (2015); V. Flauraud et al., Nat. Nanotechnol. 12, 73-80 (2017)]. To address this challenge, we have developed a synthetic strategy to precisely arrange any anisotropic colloidal nanoparticle onto a substrate using a shallow-template-assisted, DNA-mediated assembly approach. We show that anisotropic nanoparticles of virtually any shape can be anchored onto surfaces in any desired arrangement, with precise positional and orientational control. Importantly, the technique allows nanoparticles to be patterned over a large surface area, with interparticle distances as small as 4 nm, providing the opportunity to exploit light-matter interactions in an unprecedented manner. As a proof-of-concept, we have synthesized a nanocrystal-based, dynamically tunable metasurface (an anomalous reflector), demonstrating the potential of this nanoparticle-based metamaterial synthesis platform.


[Bone harvesting from the iliac crest].
Autogenous bone grafts from the iliac crest are frequently harvested for autologous bone transplantation. Although an autologous bone transplant does improve the local bone healing potency, significant donor site morbidity must be considered. In this study we elucidate special bone harvesting techniques from the iliac crest and review the literature related to clinical significance of donor site morbidity. Furthermore, our own experiences are compared and discussed critically with relevant data of other investigators. The increasing number of scientific publications which focus on bone harvesting techniques and related complications in recent years indicate the high interest and relevance of this issue. There is a tendency to alternatives such as biomaterials as bone substitutes, whereas the role of growth factors and cell therapeutics in the treatment of bony defects are still being evaluated in clinical studies. Although autologous, heterotopic bone transplantation is still the gold standard in the treatment of bony defects, there is a tendency towards the application of biomaterials, stem cells, and growth factors. Conscientious observation of relevant anatomic considerations during bone harvesting procedures may help to avoid complications.


Granulomas and cholestatic--hepatocellular injury associated with phenylbutazone. Report of two cases.
A combined cholestatic-hepatocellular injury and noncaseating granulomas occurred in two patients 1 and 4 weeks after phenylbutazone therapy. Both patients were jaundiced, one had a macular rash, and both had peripheral blood eosinophilia. Symptoms and signs subsided, and abnormal findings from tests of hepatic function rapidly returned to normal following withdrawal of the drug. Sections of liver biopsy specimens 6 months later showed no granulomas or other pathologic changes. Previously reported cases are reviewed.


An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia.
Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell-based assays, we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11 ,dTrp12 ,Trp23 ,Tyr36 ]-PTHrP(7-36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice). We observed that after 2 weeks of twice-daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof-of-concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.


Anterior surgical options for the treatment of cervical spondylotic myelopathy in a long-term follow-up study.
To provide a basis for the choice of anterior surgery procedures in the treatment of cervical spondylotic myelopathy (CSM) through long-term follow-up. A consecutive series of 89 patients with CSM having complete follow-up data were analyzed retrospectively. All patients were treated with anterior cervical discectomy and fusion (ACDF), and anterior cervical corpectomy and fusion (ACCF) from July 2000 to June 2007. The lesions were located in one segment (n = 25), two segments (n = 56), and three segments (n = 8). Preoperative and postoperative, the C2-C7 angle, cervical intervertebral height, radiographic fusion status, result of the adjacent segment degeneration, the Japanese Orthopaedic Association (JOA), and the Short Form 36-item (SF36) questionnaire scores were used to evaluate the efficacy of the surgery. According to the different compression conditions of the 89 cases, different anterior operation procedures were chosen and satisfactory results were achieved, indicating that direct anterior decompressions were thorough and effective. The follow-up period was 60-108 months, and the average was 79.6 months. The 5-year average symptom improvement rate, effectiveness rate, and fineness rate were 78.36 %, 100 % (89/89), and 86.52 % (77/89), respectively. For CSM with compression coming from the front side, proper anterior decompression based on the specific conditions could directly eliminate the compression. Through long-term follow-up, the effect of decompression became observable.


Risk factors for suboptimal vitamin D levels among adults with HIV attending an inner-city clinic of New Orleans, Louisiana.
Vitamin D insufficiency and deficiency are highly prevalent in populations with HIV, but there is limited data on predictors for suboptimal levels. To determine risk factors for Vitamin D insufficiency/deficiency, 185 charts were retrospectively reviewed. Proportions with Vitamin D levels < 10 ng/ml, 10 - 20 ng/ml, 20 - 30 ng/ml and > 30 ng/ml were 14.6%, 44.8%, 24.9%, and 15.7%, respectively. Bivariate analysis showed that Vitamin D levels < 20 ng/ml were associated with a lower albumin level (p =.02), female gender (p = .0003), and African-American (AA) race (p = .0001). Tenofovir exposure showed borderline significance (p = .09). AA race was the only significant factor in multivariate modeling. Vitamin D insufficiency/deficiency was high. AA race was an independent risk factor. Although not significant, obese persons with a poorer nutritional status and possibly those on tenofovir may also be at higher risk.


Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations.
Gaucher disease (GD) is a disorder of glycosphinglipid metabolism caused by deficiency of lysosomal acid beta-glucosidase (GC), resulting in progressive deposition of glucosylceramide in macrophages. The glucose analogue, N-butyl-deoxynojirimycin (NB-DNJ, Miglustat), is an inhibitor of the ceramide-specific glucosyltransferase (CSG) which catalyzes the first step of glycosphingolipids biosynthesis and is currently approved for the oral treatment of type 1 GD. Using site-directed mutagenesis, we constructed plasmids containing wild-type and several mutations in glucocerebrosidase (GBA) gene. The plasmids were transfected into COS-7 cells and stable transfected cell lines were obtained by geneticin (G418) selection. Cells were cultured during 6 days with medium with or without 10 microM NB-DNJ. The addition of NB-DNJ to COS-7 cell medium leads to 1.3-, 2.1-, 2.3-, 3.6-, and 9.9-fold increase in the activity of S364R, wild-type, N370S, V15M, and M123T GC, respectively. However, no significant changes were observed in the activity of the L444P, L336P, and S465del mutated proteins, but a small decrease in the rare P266L variant was observed. These results suggest that NB-DNJ, in addition to the inhibitory effect on CSG, also works as a "chemical chaperone", increasing the activity of acid beta-glucosidase of wild-type and several GC mutated proteins, including the most frequent N370S mutation. The specific location of the Miglustat binding site in GC is unknown. Potential binding sites in the enzyme have been searched for using computational molecular docking. The searching strategy identified three potential GC binding sites for Miglustat, one being the substrate-binding site of the enzyme, which was the best-ranked site by AutoDock program. Therefore, it is possible that Miglustat exerts its chaperoning activity on acid beta-glucosidase by acting as an inhibitor bound at the active site. This increase on the activity of the acid beta-glucosidase would imply that Miglustat is not only a substrate reducer but also an inhibitor of the GC degradation, with very promising clinical implications for the treatment of GD patients.


Can 'humanized' mice improve drug development in the 21st century?
Chimeric mice, which have human hepatocytes engrafted in their liver, have been used to study human drug metabolism and pharmacodynamic responses for nearly 20 years. However, there are very few examples where their use has prospectively impacted the development of a candidate medication. Here, three different chimeric mouse models and their utility for pharmacology studies are evaluated. Several recent studies indicate that using these chimeric mouse models could help to overcome traditional (predicting human-specific metabolites and toxicities) and 21st century problems (strategies for personalized medicine and selection of optimal combination therapies) in drug development. These examples suggest that there are many opportunities in which the use of chimeric mice could significantly improve the quality of preclinical drug assessment.


Predictors of Persistence of Risky Drinking in Adults: An 11-Year Follow-Up Study.
To examine the long-term predictors of persistence of risky drinking in a baseline group of risky drinkers in whom alcohol use disorder had not been diagnosed. The data was derived from a representative sample of the Finnish adult population aged 30 years or more, surveyed at 2 time points in the years 2000 (n = 5,726) and 2011 (n = 3,848, 67.2% of the baseline sample). Risky drinking was defined using BSQF-measurement (for men, 21 standard UK drinks or more per week; for women 14+ drinks) and not having alcohol abuse or alcohol dependence. The sample of risky drinkers in baseline comprised 642 persons, of whom 380 (59.2%) people provided follow-up data. Multivariable logistic regression models were estimated to identify determinants of persistence of risky drinking. The rate for persistence of risky drinking was 48.7%. Persistence was predicted by daily smoking, low physical activity, and male gender, whereas higher age and later onset of drinking predicted cessation of risky drinking. Daily smoking remained an independent predictor after adjusting for other risk factors. Health behaviour predicts the persistence of risky drinking in a study population of adults aged 30 and over. These factors should be taken into account when assessing the long-term prognosis on risky drinking.


Direct and indirect effects of maltreatment typologies on suicidality in a representative Northern Irish sample: Psychopathology only partially mediates the relationship.
There has been a rise in suicide rates among men who grew up during the 1970's in Northern Ireland (NI). Conflict exposures (CEs) have been linked with suicide ideation but not attempts. Civil conflict has also been linked with aggressive parenting which is associated with the development of aggressive drives, psychopathology and suicidality. This study investigated (1) cohort specific associations between latent classes (LCs) of maltreatment and (2) associations between LCs, CEs, psychopathology and suicidality. Data were from NI Study of Health and Stress (N = 1986). Maltreatment and suicidality were queried using validated measures. Psychiatric assessments were based on DSM-IV criteria. Logistic regression, latent class analysis, chi square tests and mediation analyses were conducted. Two at risk LCs were identified, entitled "family violence exposure" (FVE, 10.4%; Male, 55.4%) and "family violence and sexual abuse exposure" (FVSAE, 1.2%; Female, 90.5%). Both were more likely to have experienced CEs (FVE = 71%; FVSAE = 77.5%) than the low risk class. The FVE were more likely to be male; aged 35-49 and to suffer from a mental disorder. The FVSAE class all endorsed rape, were more likely to be separated and to suffer from a mental disorder. CEs uniquely predicted ideation but not enactment. Psychopathology partially mediated the relationship between LCs and suicidality. FVE and FVSAE directly increased the odds of enactment. These findings are original and highly pertinent and they should be used to inform any strategy for addressing the cohort specific and trauma related rise in suicide rates in NI.


N-(3-Chloro-benzo-yl)-3-nitro-benzene-sulfonamide.
In the title compound, C(13)H(9)ClN(2)O(5)S, the dihedral angle between the two benzene rings is 83.5 (1)°. In the crystal, mol-ecules are linked via N-H⋯O(S) hydrogen bonds into helical chains running along the b axis.


Luminescent immunodetection of western-blotted proteins from coomassie-stained polyacrylamide gel.
Immunodetection with horseradish peroxidase-linked antibodies on Coomassie-stained nitrocellulose blots can be performed efficiently and rapidly with the peroxidase substrate luminol. The luminescence produced is detected with radioautographic film. This procedure allows a direct identification of immunodetected bands of stained nitrocellulose sheets without using radiolabeled secondary antibodies. Because of its convenience and sensitivity, this method could be particularly suitable for purification of immunodetected proteins.


A neighbourhood approach to self-thinning.
The fate of individual plants of Helianthus annuus was monitored in populations sown at a density of 650 seeds m-2. Ninety six percent of the seeds germinated but only fifty two percent of the seedlings survived to the end of the experiment due to self-thinning. Whilst the seedlings emerged over only four days the cotyledons then took up to eight days to emerge from the seed case and open fully. The survival of individuals depended primarily on cotyledon-opening time but plants which occupied very small areas (<900 mm2) at germination were also less likely to survice. The increased likelihood of mortality amongst the late germinating individuals was probably as a result of shade from older, larger neighbours. It is suggested that one-sided interference for light during self-thinning will increase the importance of early establishment relative to neighbour effects in determining the survival of plants except at very high levels of crowding. The complex of environmental and genetic factors acting to maximise the growth rate of the very young seedling relative to its neighbours will clearly play an important part in determining the position of a plant in the size hierarchy of a population.


Two birds in the hand: Concurrent and switching cognitive flexibility in preschoolers.
Cognitive flexibility, the ability to think of something in more than one way, has been studied in preschoolers from two different approaches. Within executive function research, most studies operationalize cognitive flexibility using sequential tasks in which children must think of a specific stimulus first in one way and then in another way (switching cognitive flexibility). In contrast, Piagetian multiplicative classification tasks also require cognitive flexibility by asking children to consider multiple dimensions of a single stimulus at the same time. Piagetian tasks are typically inductive and require abstraction skills. Although research with Piagetian tasks suggests that children are unable to consider multiple dimensions simultaneously until they reach the concrete operational stage, there is some evidence that preschoolers can coordinate two dimensions simultaneously in deductive tasks. In this study, we examined a deductive version of a matrix completion task in which preschoolers (N = 102) were asked to consider two dimensions of a given stimulus simultaneously. We show that 4- and 5-year-olds can succeed on this task and compare children's performance on the matrix completion task with their performance on a widely used switching cognitive flexibility task, the Dimensional Change Card Sort. We discuss the implications of relating the two aspects of cognitive flexibility development.


Managing neurogenic bowel dysfunction: what do patients prefer? A discrete choice experiment of patient preferences for transanal irrigation and standard bowel management.
Most patients with bowel dysfunction secondary to neurological illness are managed by a range of nonsurgical methods, including dietary changes, laxatives, and suppository use to transanal irrigation (TAI). The aim of the present study was to explore individuals' preferences regarding TAI devices and furthermore investigate willingness to pay (WTP) for attributes in devices in the UK. A discrete choice experiment survey was conducted to evaluate the patients' perceived value of TAI devices. Attributes were selected based upon a literature review and input from clinicians. Interviews were conducted with three clinicians and the survey was developed and finalized with the input from both patients and professionals. The final attributes were "risk of urinary tract infections" (UTIs), "risk of fecal incontinence" (FI), "frequency of use", "time spent on toilet", "ease of use", "level of control/independence", and "cost". Participants were recruited by a patient panel of TAI device users in the UK. Data were analyzed using the conditional logit model whereby the coefficients obtained from the model provided an estimate of the (log) odds ratios (ORs) of preference for attributes. WTP was also estimated for each attribute. A total of 129 participants were included in the final analyses. Sixty two percent of the participants had suffered from three UTIs in the preceding year and 58% of patients reported currently experiencing FI using their current device. All attributes were significant predictors of choice. The most important attributes for participants were the "risk of FI", "frequency of use", and "risk of UTIs". Participants with bowel dysfunction regarded "risk of FI", "frequency of use", and "avoiding UTIs" as the most important features of a TAI device. These preferences are valuable in informing decision makers and clinicians regarding different bowel management solutions as well as for development of future devices.


A review of the clinical utility of INR to monitor and guide administration of prothrombin complex concentrate to orally anticoagulated patients.
The number of patients treated with oral anticoagulation (OAC) is increasing and these patients are monitored by International Normalized Ratio (INR). Bleeding complications are common and we speculate if this is related to the limitation of INR only reflecting the initiation steps of the haemostatic process. The objective of the present review was to reassess the evidence for using INR as a tool to guide administration of prothrombin complex concentrates (PCC) to OAC patients. A Medline and Cochrane database search was conducted using the following keywords: prothrombin complex concentrate, reversal of oral anticoagulation and international normalized ratio (INR). Thirty-three articles were contracted and a total of ten studies were eligible after applying inclusion and exclusion criteria encompassing only 339 patients. No consensus regarding optimal target INR value to aim for when reversing OAC was found. In three of the studies it was reported that patients reaching their target INR continued to bleed, whereas three studies reviewed reported good haemostatic response also in patients that did not reach their target INR. The present review found limited evidence for the usefulness of INR as a tool to monitor and guide reversal of OAC induced coagulopathy in patients with PCC, which is expected given that it is a plasma-based assay only reflecting a limited part of the haemostatic process.


[Tuberous sclerosis as cause of neuropathological symptoms allegedly due to smallpox vaccination (author's transl)].
Following smallpox vaccination a patient presented with neuropathological symptoms, the real cause of which was tuberous sclerosis, a congenital disease.


PCR diagnostics and monitoring of adenoviral infections in hematopoietic stem cell transplantation recipients.
After stem cell transplantation, human patients are prone to life-threatening opportunistic infections with a plethora of microorganisms. We report a retrospective study on 116 patients (98 children, 18 adults) who were transplanted in a pediatric bone marrow transplantation unit. Blood, urine and stool samples were collected and monitored for adenovirus (AdV) DNA using polymerase chain reaction (PCR) and real-time PCR (RT-PCR) on a regular basis. AdV DNA was detected in 52 (44.8%) patients, with mortality reaching 19% in this subgroup. Variables associated with adenovirus infection were transplantations from matched unrelated donors and older age of the recipient. An increased seasonal occurrence of adenoviral infections was observed in autumn and winter. Analysis of immune reconstitution showed a higher incidence of AdV infections during periods of low T-lymphocyte count. This study also showed a strong interaction between co-infections of AdV and BK polyomavirus in patients undergoing hematopoietic stem cell transplantations.


Lansoprazole-induced thrombocytopenia.
To describe a case of thrombocytopenia associated with the administration of lansoprazole. An 85-year-old white man presented with an upper gastrointestinal hemorrhage from a gastric ulcer. His platelet count was normal on admission. He was started on oral lansoprazole 60 mg twice daily and, on hospital day 2, his platelet count decreased to 102 x 10(3)/mm(3); on hospital day 3, the platelet count was 36 x 10(3)/mm(3). Lansoprazole was discontinued, and the platelet count returned to normal. He has not had any further episodes of thrombocytopenia to date. After exclusion of other causes, the onset of thrombocytopenia after administration of lansoprazole, the resolution of the adverse reaction after discontinuation of the drug, and the fact that no other medicines were introduced during this time frame lead us to believe that this was most likely an idiosyncratic thrombocytopenic response to lansoprazole. To date, this is the first reported case of what appears to be isolated thrombocytopenia associated with lansoprazole. Clinicians should be aware of the possible association of thrombocytopenia with lansoprazole and discontinue the drug if thrombocytopenia becomes apparent.


Integrative biology: linking levels of organization.
Biological systems are composed of different levels of organization. Usually, one considers the atomic, molecular, cellular, individual, population, community and ecosystem levels. These levels of organization also correspond to different levels of observation of the system, from microscopic to macroscopic, i.e., to different time and space scales. The more microscopic the level is, the faster the time scale and the smaller the space scale are. The dynamics of the complete system is the result of the coupled dynamical processes that take place in each of its levels of organization at different time scales. Variables aggregation methods take advantage of these different time scales to reduce the dimension of mathematical models such as a system of ordinary differential equations. We are going to study the dynamics of a system which is hierarchically organized in the sense that it is composed of groups of elements that can be themselves divided into further smaller sub-groups and so on. The hierarchical structure of the system results from the fact that the intra-group interactions are assumed to be larger than inter-group ones. We present aggregation methods that allow one to build a reduced model that governs a few global variables at the slow time scale.


Rat-colonic, mucus glycoprotein.
A glycoprotein was isolated from rat-colonic mucosa. Analytical ultracentrifugation studies showed the glycoprotein to be homogeneous, having an apparent molecular weight of 9.0 X 10(5); no subunits could be detected in the presence of sodium dodecyl sulfate. It contained 14% of protein and 86% of carbohydrate. The principal sugars in the glycoprotein were galactose, fucose, sialic acid, 2-acetamido-2-deoxygalactose, and 2-acetamido-2-deoxyglucose. A small proportion of mannose was also present. The glycoprotein, apart from the usual carbohydrate constituents present in mucus glycoproteins, contained sulfate, but no uronic acid. High amounts of serine and threonine, and low contents of aromatic and traces of sulfur-containing amino acids, reflect a similarity of this glycoprotein to other mammalian mucus glycoproteins; it differs, however, by its high proportions of Asx + Glx (26 mol.%). Cleavage studies with alkaline borohydride indicated O-glycosidic linkages between N-acetylhexosamine and serine, and threonine, of the peptide core in the glycoprotein. Only about one third of the serine and threonine was linked to the carbohydrate side-chains, which averaged about 22 units in length and were apparently branched.


Twelve-month Continuation of the Etonogestrel Implant in Adolescents With Polycystic Ovary Syndrome.
To identify why adolescents with polycystic ovary syndrome (PCOS) chose the etonogestrel (ENG) contraceptive implant, to determine the 12-month continuation rate, and to characterize factors related to discontinuation. Retrospective chart review of adolescents seen at a tertiary care children's hospital between July 1, 2008, and August 30, 2019, with PCOS diagnosis confirmed per National Institutes of Health criteria and ≥12-month ENG follow-up. Demographic characteristics, reasons for ENG insertion and removal, and information on other hormonal/contraceptive therapies were collected. Patients were categorized as ENG continuers (use ≥12 months) or discontinuers (removal at <12 months), and groups were compared. A total of 96 patients met inclusion criteria (age 17.7 ± 2.2 years, body mass index 34.8 ± 8 kg/m2). Reasons for ENG were documented in 74% (51% contraception, 32% ease of use, 15% other, 13% estrogen avoidance). In all, 27% had never been sexually active, and 67% had had prior sexual activity. Treatments prior to ENG placement included 74% combined hormonal contraception, 20% medroxyprogesterone acetate withdrawal, and 17% depot medroxyprogesterone. A total of 77% continued ENG at 12 months. The main reasons for discontinuation were bleeding (41%), concern about weight gain (23%), and mood changes (18%). No preimplantation characteristics were independently predictive of continuation, although 100% of patients with type 2 diabetes (n = 11) continued. Patients who sought additional care, including telephone calls (41% vs 12%, P = .006) and clinic visits (64% vs 20%, P < .001) were more likely to discontinue. The ENG implant was well tolerated in adolescents with PCOS and similar to published 12-month continuation rates.


Spectrochemical analysis of blood combined with chemometric techniques for detecting osteosarcopenia.
Among several complications related to physiotherapy, osteosarcopenia is one of the most frequent in elderly patients. This condition is limiting and quite harmful to the patient's health by disabling several basic musculoskeletal activities. Currently, the test to identify this health condition is complex. In this study, we use mid-infrared spectroscopy combined with chemometric techniques to identify osteosarcopenia based on blood serum samples. The purpose of this study was to evaluate the mid-infrared spectroscopy power to detect osteosarcopenia in community-dwelling older women (n = 62, 30 from patients with osteosarcopenia and 32 healthy controls). Feature reduction and selection techniques were employed in conjunction with discriminant analysis, where a principal component analysis with support vector machines (PCA-SVM) model achieved 89% accuracy to distinguish the samples from patients with osteosarcopenia. This study shows the potential of using infrared spectroscopy of blood samples to identify osteosarcopenia in a simple, fast and objective way.


[Laparoscopically assisted vaginal hysterectomy Gasless. Retrospective study in patients with uterine fibroids].
To evaluate the feasibility to perform laparoscopically assisted vaginal hysterectomy in patients who were not suitable for vaginal hysterectomy. LAVH Gasless was carried out on 31 patients with uterine fibroids. Uterine weight ranged of 420-800 gr. There were 2 laparotomy conversion (6%) for uterus 800 gr; median operating time was 79 +/- 18 minutes (range 75-89); the average haemoglobin drop was 1.7 +/- 0.9 g/dl; the mean in postoperative stay was 3.7 +/- 0.7 days (range 3-5). Febrile morbidity > 38 degrees C were found in 3 cases. Laparoscopic assistance has advantages in performing transection of round and infundibolo-pelvic ligaments in vaginal steps and in controlling post-operative blood loss.


The Jülich Environmental Specimen Bank.
The environmental specimen bank of the Federal Republic of Germany represents the modern form of a systematically designed archive for the preservative storage of selected environmental specimens. Major aims of environmental specimen banks are: (i) retrospective identification and quantification of environmental chemicals including those not known at the time of storage; (ii) retrospective replicate analysis of samples stored under preservative conditions for the determination of inorganic elements or organic compounds already examined; and (iii) retrospective control of the success of legislative environmental protection measures in handling chemicals regarded as hazardous for man and the environment. Results of the environmental specimen bank at Jülich by the Institute of Applied Physical Chemistry, Research Centre Jülich, KFA, obtaining the initiated legislative regulations providing environmental pollution, are already proved for various compartments.


The dynamics of gas bubbles in conduits of vascular plants and implications for embolism repair.
Pressure-induced tensions in the xylem, the water conducting tissue of vascular plants, can lead to embolism in the water-conducting cells. The details and mechanisms of embolism repair in vascular plants are still not well understood. In particular, experimental results which indicate that embolism repair may occur during xylem tension cause great problems with respect to current paradigms of plant water transport. The present paper deals with a theoretical analysis of interfacial effects at the pits (pores in the conduit walls), because it was suggested that gas-water interfaces at the pit pores may be involved in the repair process by hydraulically isolating the embolized conduit. The temporal behaviour of bubbles at the pit pores was especially studied since the question of whether these pit bubbles are able to persist is of crucial importance for the suggested mechanism to work. The results indicate that (1) the physical preconditions which are necessary for the suggested mechanism appear to be satisfied, (2) pit bubbles can achieve temporal stability and therefore persist and (3) dissolving of bubbles in the conduit lumen may lead to the final breakdown of the hydraulic isolation. The whole process is, however, complex and strongly dependent on the detailed anatomy of the pit and the contact angle.


Assessment of cyclosporin A in whole blood and plasma in five patients with different hematocrits.
Measurement of whole blood and plasma levels of cyclosporin A (CsA) by radioimmunoassay in kidney transplant recipients receiving the drug showed that CsA concentrations in plasma increased nonlinearly when whole blood levels of the drug exceeded 1,000 ng/ml. At low plasma levels (less than 200 ng/ml), most of the CsA in the blood was in the nonplasma component, indicating that cellular elements have high affinity for CsA. Comparison of nonplasma CsA concentrations in two patients with hematocrit values of 32.5 and 35% showed that in the patient with a hematocrit of 35% the cellular associated drug was twice as great as that in the other patient, indicating that there may be significant differences in the cellular affinity of CsA in patients with similar hematocrits. Linear regression analysis of the cellular associated CsA versus plasma levels of the drug in a double-reciprocal plot showed a drug saturation capacity of 6,060 ng/ml in the nonplasma component of blood in the patient with a hematocrit of 35%. Similar analyses in the other patients indicated saturation capacities ranging from 4,750 to 10,400 ng/ml.


Microbial serine protease inhibitors and their therapeutic applications.
Serine protease inhibitors, inhibit serine proteases either partially or completely after forming complexes with their respective proteases. Protease actions are significant for many physiological pathways found in living forms and any anomalies may lead to numerous physiological complications. Each cell or organism has its own mechanism for controlling these protease actions. It is often regulated by the action of inhibitors or activators. Among the proteases, serine proteases are the most common that are involved in many life and death processes. Selective inhibitors of physiologically relevant proteases can be used as a lead compound for the drug development. Therefore, it is imperative to identify small peptides and proteins that selectively inhibit serine proteases from various sources. Microbes can be considered as a major source of diverse serine protease inhibitors since they have the prominent and diverse domain in nature. Most of the microbial serine protease inhibitors are intracellular and few are extracellular. Microbes produce protease inhibitors for protection against its own proteases or against other environmental factors. The status and future prospects of microbial serine protease inhibitors and their therapeutic benefits in treating cancer, blood coagulation disorders and viral infections, are reviewed here.


The metabolic syndrome in smokers. The D.E.S.I.R. study.
To test the hypothesis that smokers have a higher frequency of the metabolic syndrome, and a syndrome with different characteristics than non-smokers. The 2,569 men and 2,637 women included in the D.E.S.I.R. study, aged 30-64 years, volunteers from ten French Social Security Health Examination Centres, were studied. The World Health Organization definition of the metabolic syndrome was adapted for this analysis, and insulin resistance was defined by a concentration above the 75(th) centile of the sex-specific distribution of fasting insulin. 28.1% of men and 15.1% of women were current smokers. The metabolic syndrome was twice as frequent in men than in women (22.8% vs 11.0%). Smokers and never-smokers were compared in age stratified samples. In men, the frequencies of hyperglycaemia or hypoglycaemic treatment, dyslipidaemia, microalbuminuria, and central obesity were significantly higher in smokers and 22.5% of smokers and 15.3% of non-smokers had this syndrome (p=0.001). In women, only dyslipidaemia was more frequent in smokers; in contrast smokers had lower insulin concentrations and hence a lower frequency of hyperinsulinemia. The frequency of the syndrome did not differ between women who smoked and those who did not (6.3% vs 6.0%). In men, the metabolic syndrome was more frequent in smokers than in non-smokers; in contrast, there was no difference for women. For both sexes, syndrome abnormalities tended to be more frequent in smokers than in non-smokers.


A double-blind, placebo-controlled study comparing three single-dose regimens of piroxicam with ibuprofen in patients with primary dysmenorrhea.
Sixty-eight women with primary dysmenorrhea were randomly assigned to one of five four-times-daily treatment groups for a minimum of three days and a maximum of five days. Three of the groups received different initial single-daily doses of piroxicam, which were followed on each treatment day with placebo for the second through fourth doses, namely, piroxicam 20 mg daily for five days (piroxicam 20 mg for five days); piroxicam 40 mg on Day 1, followed by piroxicam 20 mg on Days 2 through 5 (piroxicam 40 mg for one day); and piroxicam 40 mg on Days 1 and 2, followed by piroxicam 20 mg on Days 3 through 5 (piroxicam 40 mg for two days). The fourth group received ibuprofen 400 mg four times per day, and the fifth group received placebo four times per day. Patients determined the severity of overall discomfort and pelvic-abdominal pain at baseline and prior to each dose using a four-point numerical scale. Supplemental ibuprofen, 400 mg four times per day, was provided for those patients requiring additional pain relief. Patients also made a global determination of overall relief at the end of the study. At 24 hours, the results revealed that piroxicam 40 mg for two days, piroxicam 20 mg for five days, and ibuprofen provided significantly more relief of overall discomfort compared with placebo (p = 0.003, p = 0.018, and p = 0.026, respectively). All four active treatment groups also experienced significantly more relief of pelvic-abdominal pain compared with placebo: piroxicam 40 mg for two days followed by three days of 20 mg (p = 0.002), piroxicam 40 mg for one day followed by four days of 20 mg (p = 0.023), piroxicam 20 mg for five days (p = 0.012), and ibuprofen (p = 0.011). A significantly smaller percentage of patients treated with piroxicam 40 mg for two days required supplemental medication as compared with those treated with piroxicam 20 mg for five days (p = 0.035) and patients treated with placebo (p = 0.010). A greater amount of overall relief was obtained by patients treated with piroxicam 40 mg for two days compared with patients treated with piroxicam 40 mg for one day (p = 0.041) and placebo-treated patients (p = 0.001). It was concluded that single daily doses of piroxicam 20 mg and 40 mg were as effective as ibuprofen, 400 mg four times per day, for the relief of primary dysmenorrhea.


Conjunctival lymphoma: results and treatment with a single anterior electron field. A lens sparing approach.
Lymphoma of the conjunctiva is rare. It presents in older patients as a mass lesion and usually remains localized. Surgery is limited to biopsy, and radiation therapy is the definitive treatment of choice. The entire conjunctiva is treated. Relatively high doses (approximately 30 Gy) are required for local control, which may lead to cataract formation. Twelve patients with conjunctival lymphoma were treated at the Massachusetts General Hospital between 1979 and 1988. Ten of 12 patients presented with a unilateral lesion; 2 of 12 with bilateral lesions. Two of 12 patients were found to have systemic disease at the time of presentation. One patient developed conjunctival lymphoma 5 years after the diagnosis of generalized disease. Using electron beam, all patients were treated with a single anterior circular field to total doses ranging from 24 Gy to 30 Gy delivered in 8 to 16 fractions over 9 to 20 days. In all cases, the lens was shielded by a specially designed plastic contact lens bearing a 12 mm diameter lead shield. The lens dose was determined at varying depths beneath the shield for 6 MeV and 9 MeV electron beams and ranged from a minimum of 5% to an absolute maximum of 18% of the total dose delivered to the tumor. Local control was maintained in all patients with follow-up to 9 1/2 years. One patient relapsed distantly 3 years after treatment. One of 12 patients died of systemic disease 4 years after treatment of the ocular lesion. Two patients developed cataracts 4 and 5 years after treatment; one had bilateral cataract, although only one eye had been treated. Both patients were over 75 years old. In both cases, the cataracts were felt to be senile cataracts which are ophthalmologically and radiographically distinguishable from radiation induced lesions.


Use of genetically engineered lipid-tagged antibody to generate functional europium chelate-loaded liposomes. Application in fluoroimmunoassay.
Biosynthetically lipid-tagged single-chain antibody (Laukkanen et al., Protein Eng. 6 (1993) 449; Biochemistry 33 (1994) 11664) has been used to functionalize europium (Eu3+) chelate-loaded liposomes. The resulting Eu immunoliposomes displayed specific hapten-binding activity and little non-specific binding in time-resolved fluoroimmunoassay (TR-FIA). No loss of entrapped marker nor of binding activity was observed after storage of Eu immunoliposomes for 1 month at 4 degrees C. In comparison with Eu-labeled free single-chain antibody, Eu immunoliposomes produced a higher signal and provided increased sensitivity in a sandwich-type immunoassay. These results demonstrate the potential of Eu immunoliposomes as signal-amplifying reagents in TR-FIA.


Looking Back to Move Forward: The Current State of Research on the Clinical Applications of Camphor- and Menthol-Containing Agents.
Topically applied compounds containing camphor and menthol have been used to alleviate pain, cold symptoms, and pruritus, historically predominantly in East Asia. Being not studied well, they are less recognized in Western medicine. Given the commonality of pain, pruritus, and cold symptoms in addition to the growing need for non-opioid treatment options, the authors investigated clinical applications of such compounds for their over-counter usage. The purpose was to analyze current clinical research and applications regarding the use of these topical agents. This study involved a bibliometric analysis of peer-reviewed articles, published in English and indexed in PubMed from 2010 to 2022, pertaining to camphor- and menthol-containing compounds. There were 103 results, of which 15 (14.6%) articles were related to the treatment of disorders related to health, such as upper respiratory infection, pain, and pruritus. Excluded were "non-research" articles (e.g., letters to the editor), articles that do not involve human subjects, reports of improper application or misuse (e.g., ingestion), and articles pertaining to intraoral, intranasal, and ophthalmic agents. Of these articles, the originating journals, respective journal impact factor scores, publication years, study designs, and study topics were identified. Underlying trends and themes regarding clinically relevant research on these compounds were subsequently discerned. Based on this analysis, topical agents containing camphor and menthol are potentially effective at treating pain, upper respiratory infection symptoms, and pruritus in addition to potentially functioning as an antimicrobial. However, with a limited number of studies addressing these compounds' uses in each application, no definitive recommendation can be made regarding their use. Given the promising results of earlier studies, the authors recommend that more primary research, particularly randomized, double-blind controlled studies, be done regarding clinical applications of these substances.


Analysis of detached human kinetochores.
A method has recently been established for inducing the physical detachment of kinetochores from chromosomes in human HeLa cells, and was used in the studies reported here to investigate the organization and function of dissociated HeLa kinetochores. Immunofluorescence labeling demonstrated that the detached HeLa kinetochores were relatively intact, with the number of detached kinetochores being only moderately more than the diploid number of chromosomes in HeLa cells. In addition, the detached kinetochores could be labeled with antibodies specific for the inner kinetochore plate, outer kinetochore, and subjacent centromeric heterochromatin. A functional assay demonstrated that detached kinetochores retained the capacity to activate the spindle checkpoint, leading to metaphase arrest. Analysis of kinetochore DNA indicated that it consisted primarily of DNA fragments of 130-160 kb in size, while the remainder of the chromosomes were sheared into much smaller fragments during the kinetochore detachment event. Further analysis of kinetochore DNA indicated that it was first cleaved into high molecular weight DNA (>200 kb) fragments during the initial stages of the kinetochore detachment process, and then underwent further maturation following nuclear envelope breakdown to give rise to the 130-160 kb fragment in detached kinetochores. Collectively, these data indicate that detached human kinetochores will be a useful system for investigating the organization, assembly, and function of human kinetochores.


[Diagnostic image (74) A woman with stomach cramps and vomiting].
In a 53-year-old woman with abdominal pain, nausea and vomitus lasting for a month and leading to weight loss, abdominal CT showed abdominal spigelian hernia.