Proximal tibial osteophytes and their relationship with the height of the tibial spines of the intercondylar eminence: paleopathological study.
Tibial spiking (i.e., spurring of tibial spines), eburnation, and osteophytes are considered features of osteoarthritis. This investigation employed direct inspection of the medial and lateral tibial plateaus in paleopathological specimens to analyze the frequency and morphological features of osteoarthritis and to define any relationship between the size of osteophytes and that of the intercondylar tibial spines. A total of 35 tibial bone specimens were evaluated for the degree of osteoarthritis and presence of eburnation. Each plateau was also divided into four quadrants and the presence and size of bone outgrowths were recorded in each quadrant. The "medial/lateral tibial intercondylar spine index" for each specimen was calculated as follows: (medial/lateral intercondylar tibial spine height)/(anteroposterior width of the superior tibial surface). The relationships between medial and lateral tibial height indexes with the degree of osteoarthritis were then tested. Osteophytes were observed more frequently in the anterior quadrants of both tibial plateaus than in the posterior quadrants (29 vs 16 for the medial tibial plateau [p = 0.01] and 28 vs 20 for the lateral tibial plateau [p = 0.04]). Eburnation was seen more frequently in the posterior regions of both tibial plateaus than in the anterior regions (17 vs 5, p < 0.01). In specimens with no signs of osteoarthritis the lateral intercondylar tibial index was significantly lower than that in specimens with some degree of osteoarthritis (p = 0.02). The medial intercondylar tibial index of the specimens with no signs of osteoarthritis was not significantly different from that of the specimens with some degree of osteoarthritis (p = 0.45). There was a positive correlation between the lateral spine height index and the overall grading of osteoarthritis, (r = 0.6, p < 0.01). In the anteromedial and posteromedial quadrants of the lateral tibial plateau, the association between the lateral intercondylar tibial spine index and the grade of osteophytes was 0.5 (p < 0.01) and 0.7 (p < 0.01) respectively. Spiking of the lateral tibial intercondylar spine is associated with osteophyte formation and osteoarthritis. Eburnation occurs mainly in the posterior parts of the tibial plateaus while osteophytes arise mainly in the anterior parts. These findings suggest that stresses occurring in the flexed knee may contribute to many of the morphological abnormalities of osteoarthritis.


Introduction to Pediatric Sepsis.
Sepsis is a significant health problem in both critically ill children and adults. While the mortality rate from sepsis is much lower in children, sepsis is directly responsible for over 4,000 childhood deaths per year in the United States alone. At face value, this number suggests that more children die per year in the United States from sepsis as the primary cause than from cancer. Unfortunately, there are few studies on the epidemiology, pathophysiology, and management of sepsis in children. Moreover, extrapolation of adult data to critically ill children is probably not appropriate due to several key developmental differences in the host response to infection and response to therapy. Therefore, additional studies targeting sepsis in the pediatric population are urgently required.


Differential impact of body mass index and its change on the risk of breast cancer by molecular subtype: A case-control study in Japanese women.
Body mass index (BMI) is an independent risk factor for luminal-type breast cancer in Western populations. However, it is unclear whether the impact of BMI differs according to breast cancer subtype in Japanese populations. We conducted a case-control study with 715 cases and 1430 age- and menopausal status-matched controls to evaluate the associations of BMI and its change (from age 20 years to the current age) with breast cancer risk. We applied conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tumor subtypes were divided into four subtypes, namely the luminal, luminal/HER2, HER2-rich, and triple-negative subtypes. Current BMI and BMI change were positively associated with postmenopausal breast cancer risk. On stratified analysis by tumor subtype, we observed associations between current BMI and BMI change and postmenopausal breast cancer risk for the luminal subtype, with OR for each 1 kg/m(2) increase in current BMI of 1.14 (95% CI: 1.07 - 1.20) and the corresponding OR of BMI change of 1.16 (1.09 - 1.23) (each P(trend) < 0.001). Additionally, we found the same tendency for the triple-negative subtype, with the OR for a 1 kg/m(2) increase in current BMI of 1.21 (1.05 - 1.39) and that for BMI change of 1.18 (1.02 - 1.36) (P(trend) was 0.008 and 0.024, respectively). In premenopausal women, a suggestive inverse association was observed between BMI change and breast cancer risk for the luminal subtype only, with OR of BMI change of 0.93 (0.87 - 1.00, P(trend) = 0.054). No association was seen between BMI at age 20 years and risk of any tumor subtype. In conclusion, BMI and its change are associated with the risk of both luminal and triple-negative breast cancer among postmenopausal Japanese women. These findings suggest the etiological heterogeneity of breast cancer among tumor subtypes. The online version of this article (doi:10.1186/2193-1801-1-39) contains supplementary material, which is available to authorized users.


Roles of glycosylation in Notch signaling.
Notch and the DSL Notch ligands Delta and Serrate/Jagged are glycoproteins with a single transmembrane domain. The extracellular domain (ECD) of both Notch receptors and Notch ligands contains numerous epidermal growth factor (EGF)-like repeats which are post-translationally modified by a variety of glycans. Inactivation of a subset of genes that encode glycosyltransferases which initiate and elongate these glycans inhibits Notch signaling. In the formation of developmental boundaries in Drosophila and mammals, in mouse T-cell and marginal zone B-cell development, and in co-culture Notch signaling assays, the regulation of Notch signaling by glycans is to date a cell-autonomous effect of the Notch-expressing cell. The regulation of Notch signaling by glycans represents a new paradigm of signal transduction. O-fucose glycans modulate the strength of Notch binding to DSL Notch ligands, while O-glucose glycans facilitate juxta-membrane cleavage of Notch, generating the substrate for intramembrane cleavage and Notch activation. Identifying precisely how the addition of particular sugars at specific locations on Notch modifies Notch signaling is a challenge for the future.


Functional and nutritional outcomes after gastric cancer surgery.
Recent improvements in diagnostic techniques and national screening programs have resulted in increasing number of patients diagnosed with early gastric cancer (EGC). The low incidence rate of lymph node metastasis and excellent survival rates after surgical treatment for EGC enabled the reduction in the extent of lymphadenectomy and the range of gastric resection for function-preserving gastrectomy. Thus, the quality of life (QOL) of patients with gastric cancer (GC) in the curative stage can be maintained. Moreover, these function-preserving procedures have been widely performed by less invasive procedures, such as laparoscopic and robotic approaches. Pylorus-preserving gastrectomy (PPG) and proximal gastrectomy (PG) represent the two main function-preserving surgical procedures for GC. PPG is an alternative to distal gastrectomy (DG) for cT1 N0 EGC located in the middle part of the stomach. Preservation of the pyloric function is expected to prevent post-gastrectomy syndromes such as dumping syndrome. PG is an alternative to total gastrectomy (TG) and can thus be performed for cT1 N0 EGC located in the upper part of the stomach. Preservation of the residual stomach is expected to work as a reservoir for ingested food. The optimal reconstruction method after PG among the three most commonly performed procedures (esophagogastrostomy, jejunal interposition, and double-tract reconstruction) remains controversial. In addition to these three reconstruction methods, the novel double-flap technique (DFT) of esophagogastrostomy has gained attention recently because of its potential usefulness to prevent postoperative esophageal reflux. In this review article, we summarize the current evidence of PPG and PG with esophagogastrostomy by the DFT, focusing on postoperative nutrition and QOL.


The reproductive season of scleractinian corals in Socotra, Yemen.
Determining when corals reproduce has clear management and economic implications. Here we document the reproductive condition of corals in the genus Acropora on the island of Socotra in Yemen during February 2014. Twenty percent of colonies (n = 143) contained mature gametes and 28% had immature gametes indicating that spawning will occur in both February and March in 2014, confirming previous anecdotal reports of coral spawning at this time in Socotra. Acropora typically reproduce in synchrony with many other broadcast spawning scleractinian corals, and we therefore predict that many other species are reproductively active at this time of year.


The Structural Basis of IRF-3 Activation upon Phosphorylation.
The innate immune system is the first line of defense against bacterial and viral infections. The recognition of pathogen-associated molecular patterns by the RIG-I-like receptors, TLRs, and cGAS leads to the induction of IFN-I by activating the transcription factor IRF-3. Although the mechanism of IRF-3 activation has been extensively studied, the structural basis of IRF-3 activation upon phosphorylation is not fully understood. In this study, we determined the crystal structures of phosphorylated human and mouse IRF-3 bound to CREB-binding protein (CBP), which reveal that phosphorylated IRF-3 forms a dimer via pSer386 (pSer379 in mouse IRF-3) and a downstream pLxIS motif. Size-exclusion chromatography and cell-based studies show that mutations of key residues interacting with pSer386 severely impair IRF-3 activation and IFN-β induction. By contrast, phosphorylation of Ser396 within the pLxIS motif of human IRF-3 only plays a moderate role in IRF-3 activation. The mouse IRF-3/CBP complex structure reveals that the mechanism of mouse IRF-3 activation is similar but distinct from human IRF-3. These structural and functional studies reveal the detailed mechanism of IRF-3 activation upon phosphorylation.


Fluorescence quenching study of melittin-membrane interactions.
The bee venom peptide melittin is a popular object for studying lipid-protein interactions. In this paper we show that binding of melittin to the bilayer is a complex process involving several steps. We were able to resolve those steps by utilizing a new approach in the quantitative analysis of depth-dependent fluorescence quenching in membranes. The "distribution analysis" technique (DA) employed here provides not only the most probable depth of the fluorophore but also allows the estimation of its conformational heterogeneity and accessibility to the lipid phase. A model for melittin interaction with the membranes is suggested.


Molten salt-assisted synthesis of bismuth nanosheets with long-term cyclability at high rates for sodium-ion batteries.
Bismuth is a promising anode material for sodium-ion batteries (SIBs) due to its high capacity and suitable working potential. However, the large volume change during alloying/dealloying would lead to poor cycling performance. Herein, we have constructed a 3D hierarchical structure assembled by bismuth nanosheets, addressing the challenges of fast kinetics, and providing efficient stress and strain relief room. The uniform bismuth nanosheets are prepared via a molten salt-assisted aluminum thermal reduction method. Compared with the commercial bismuth powder, the bismuth nanosheets present a larger specific surface area and interlayer spacing, which is beneficial for sodium ion insertion and release. As a result, the bismuth nanosheet anode presents excellent sodium storage properties with an ultralong cycle life of 6500 cycles at a high current density of 10 A g-1, and an excellent capacity retention of 87% at an ultrahigh current rate of 30 A g-1. Moreover, the full SIBs that paired with the Na3V2(PO4)3/rGO cathode exhibited excellent performance. This work not only presents a novel strategy for preparing bismuth nanosheets with significantly increased interlayer spacing but also offers a straightforward synthesis method utilizing low-cost precursors. Furthermore, the outstanding performance demonstrated by these nanosheets indicates their potential for various practical applications.


[Blood cholinesterase in rats with experimental thyrotoxicosis and hypothyroidism].
Changes in the sum total activity of cholinesterase of the plasma and erythrocytes (AC substrate) and also separately of acetyl- and pseudocholinesterase (MeC and ByC substrates) were studied in experiments on rats with thyrotoxin toxicosis and 6-methylthiouracil hypothyroidism. The sum total activity of cholinesterase proved to increase in the erythrocytes of rats with thyrotoxicosis and fell in the erythrocytes and plasma of animals with hypothyroidism. The activity of acetylcholinesterase of erythrocytes and plasma increased in thyrotoxicosis and decreased in hypothyroidism. The activity of pseudocholinesterase of erythrocytes and plasma decreased in thyrotoxicosis and showed no significant difference in hypothyroidism.


The challenge of practice based research: a group approach.
Social work research has long been an area overlooked by direct practice clinicians for several reasons. Some clinicians are uncomfortable with research and tend to avoid it, while others feel they do not have time to generate quality research material and still serve clients adequately. The Social Work Services Department in a university teaching hospital accepted the challenge of combining direct practice and research. By drawing on internal levels of expertise, while collaborating with other area professionals, the Research Committee has adopted a group approach of individuals conducting practice-based research. This method of generating research has yielded many positive results.


Amicus or adversary: platelets in lung biology, acute injury, and inflammation.
Platelets are the chief effector cells in hemostasis and have additional major functions in inflammation, vascular integrity, and tissue repair. Platelets and the lungs have interrelated activities. Previous studies provide evidence that platelets contribute to pulmonary vascular barrier function and are required for defense against pulmonary hemorrhage, and that the lungs can influence platelet number and distribution. There is also evidence that platelets contribute to pathologic syndromes of pulmonary inflammation and thrombosis. Thus, platelets have an "amicus or adversary" relationship with the lung. Recent observations and discoveries have established new paradigms relevant to influences of platelets on lung cell and molecular biology. These new findings are in a variety of areas including thrombopoieis, nontraditional activities of platelets, new synthetic capabilities and mechanisms of post-translational gene expression, interactions of platelets with endothelial cells and contributions to alveolar capillary barrier permeability, interactions of platelets with myeloid leukocytes, and platelet involvement in stem cell signaling and vascular repair. These issues are considered in a translational approach, with an emphasis on acute lung injury and the acute respiratory distress syndrome.


Interdisciplinary treatment of an adolescent with unilateral cleft lip and palate.
The present case report describes the importance of interdisciplinary approach and gives an understanding on management of an adolescent with unilateral cleft lip and palate. Failure of fusion between medial nasal process and maxillary process or between the palatal process leads to the formation of clefts. Clefts are result of genetic or environmental factors or a combination of both. Common dental problems associated with clefts includes anterior and posterior crossbites, hypodontia, malformation and abnormal eruption pattern. A girl, aged 15 years reported with a chief complaint of unesthetic appearance of her maxillary anterior teeth. She had unilateral cleft lip and palate and had received cheiloplasty and palatoplasty when she was in young age and rhinoplasty when she was 14 years of age. At pretreatment evaluation, she had concave profile with maxillary arch constriction and oroantral fistula and mesially tipped maxillary left canine. This patient's treatment was unconventional, but it was successful in significantly improving her masticatory function and smile, along with favorable dental and facial results. Generalized esthetics and function were significantly improved in this patient without orthognathic surgery, and treatment results were stable 3 years after the appliance removal. Clinical considerations, sequencing of treatment phases as shown in this case report can be utilized while treating an adolescent with cleft lip and palate. If the skeletal discrepancy is mild and esthetic concerns are minimal, dental compensation by orthodontic treatment alone might be recommended. The cephalometric analysis and prediction tracings provide further information for deciding whether a patient can be treated by orthodontics alone, or by orthodontics and an orthognathic surgical procedure. A change in axial inclination of the teeth can camouflage the skeletal relationship adequately. However, one should be cautious in a growing patient, because he or she might outgrow the dental correction so that ultimately skeletal surgery would be indicated.


Impact of biotic interactions on the survival of emerging pathogen Acinetobacter baumannii in aquatic media.
Acinetobacter baumannii is an opportunistic pathogen causing infections in immunocompromised patients. Recent studies recorded its persistence in a variety of abiotic conditions, but data regarding the biotic interactions with other microorganisms are limited. The aim was to assess the interaction of clinically relevant A. baumannii with common faecal bacteria Escherichia coli and Enterococcus faecium. Additionally, the interaction with a bdelloid rotifer Adineta vaga as a potential agent for biological control of A. baumannii was examined. Experiments were conducted in nutrient-poor spring water (SW) and nutrient-rich diluted nutrient broth (DNB) at 22 °C. A. baumannii coexisted with E. coli and E. faecium in both media, suggesting the absence of inter-bacterial competition in long-term survival. No difference in the survival of pandrug-resistant, extensively drug-resistant or antibiotic sensitive isolates of A. baumannii was observed. Rotifers contributed to the removal of all tested bacteria, particularly in SW. Rotifers were able to remove 5.5 ± 1.3 log CFU/mL of A. baumannii in SW and 3.5 ± 1.7 log CFU/mL in DNB. Additionally, no intracellular growth of A. baumannii inside A. vaga was detected. In wastewater treatment plants and drinking water facilities, grazing by rotifers might be useful for the removal of emerging human pathogens such as A. baumannii from water.


Elevated levels of proteolytic enzymes in the aging human vitreous.
To identify whether aging of human vitreous is accompanied by an elevation in degradative enzymes within the tissue. Human vitreous samples from donors aged 10 to 88 years were placed in two groups based on donor age of less than or more than 50 years. Homogenized samples were analyzed by gelatin substrate zymography for matrix metalloproteinases (MMP). Serine proteinases were detected by casein substrate zymography, and a specific antibody was used to confirm the identity of, and to quantify, the serine proteinase, plasmin. Progelatinase A (ProMMP-2) was present in all the vitreous samples but did not show an age-related increase. MMP-2 was also present at low levels. Progelatinase B (ProMMP-9) was found in approximately 80% of samples analyzed, but neither its presence nor level of activity was age dependent. Of the serine proteinase activities detected, an enzyme of approximately 80 kDa was identified by Western blot analysis as plasmin(ogen). Quantitative analysis revealed a significant increase in plasmin(ogen) with age. This study shows there is an age-related increase in potential degradative activity in human vitreous that may be responsible for degenerative changes such as vitreous liquefaction. The data suggest that increased levels of these enzymes precede, or are indicative of, underlying ocular disease in some individuals.


Paternal investment and status-related child outcomes: timing of father's death affects offspring success.
Recent work in human behavioural ecology has suggested that analyses focusing on early childhood may underestimate the importance of paternal investment to child outcomes since such investment may not become crucial until adolescence or beyond. This may be especially important in societies with a heritable component to status, as later investment by fathers may be more strongly related to a child's adult status than early forms of parental investment that affect child survival and child health. In such circumstances, the death or absence of a father may have profoundly negative effects on the adult outcomes of his children that cannot be easily compensated for by the investment of mothers or other relatives. This proposition is tested using a multigenerational dataset from Bangalore, India, containing information on paternal mortality as well as several child outcomes dependent on parental investment during adolescence and young adulthood. The paper examines the effects of paternal death, and the timing of paternal death, on a child's education, adult income, age at marriage and the amount spent on his or her marriage, along with similar characteristics of spouses. Results indicate that a father's death has a negative impact on child outcomes, and that, in contrast to some findings in the literature on father absence, the effects of paternal death are strongest for children who lose their father in late childhood or adolescence.


Genome-wide haplotype changes produced by artificial selection during modern rice breeding in Japan.
During the last 90 years, the breeding of rice has delivered cultivars with improved agronomic and economic characteristics. Crossing of different lines and successive artificial selection of progeny based on their phenotypes have changed the chromosomal constitution of the ancestors of modern rice; however, the nature of these changes is unclear. The recent accumulation of data for genome-wide single-nucleotide polymorphisms (SNPs) in rice has allowed us to investigate the change in haplotype structure and composition. To assess the impact of these changes during modern breeding, we studied 177 Japanese rice accessions, which were categorized into three groups: landraces, improved cultivars developed from 1931 to 1974 (the early breeding phase), and improved cultivars developed from 1975 to 2005 (the late breeding phase). Phylogenetic tree and structure analysis indicated genetic differentiation between non-irrigated (upland) and irrigated (lowland) rice groups as well as genetic structuring within the irrigated rice group that corresponded to the existence of three subgroups. Pedigree analysis revealed that a limited number of landraces and cultivars was used for breeding at the beginning of the period of systematic breeding and that 11 landraces accounted for 70% of the ancestors of the modern improved cultivars. The values for linkage disequilibrium estimated from SNP alleles and the haplotype diversity determined from consecutive alleles in five-SNP windows indicated that haplotype blocks became less diverse over time as a result of the breeding process. A decrease in haplotype diversity, caused by a reduced number of polymorphisms in the haplotype blocks, was observed in several chromosomal regions. However, our results also indicate that new haplotype polymorphisms have been generated across the genome during the breeding process. These findings will facilitate our understanding of the association between particular haplotypes and desirable phenotypes in modern Japanese rice cultivars.


Common origin of pigment cells.
The fundamentally diverse vertebrate pigment cells, melanophores, xanthophores, and iridophores, contain pigmentary organelles known, respectively, as melanosomes, pterinosomes, and reflecting platelets. Their pigments are mealanins pteridines, and purines. Mosaic pigment cells containing more than one type of organelle have been observed and mosaic organelles containing more than one type of pigment have been discovered. It is proposed that the various pigment cells are derived from a stem cell that contains a primordial organelle of endoplasmic reticular origin. This primordial organelle can differentiate into any of the known pigmentary organelles.


Neonatal Withdrawal Syndrome following Late in utero Exposure to Selective Serotonin Reuptake Inhibitors: A Systematic Review and Meta-Analysis of Observational Studies.
A clear picture of neonatal withdrawal signs due to in utero selective serotonin reuptake inhibitor (SSRI) exposure and its consequences is still missing. A systematic review and a meta-analysis were performed to provide an overview of neonatal withdrawal signs following late in utero exposure to SSRIs and to quantify the corresponding risks. MEDLINE, Web of Science, and Embase were searched from inception to January 2021. The Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. English-language observational studies reporting on acute postpartum outcomes following late in utero exposure to SSRIs or SSRIs/venlafaxine were evaluated. Of 2,269 citations reviewed, 79 studies were assessed for eligibility; 13 were included in the qualitative analysis of the literature, which allowed us to identify 26 signs. A meta-analysis was run separately for studies on SSRI exposure (n = 3) and those on SSRI/venlafaxine exposure (n = 6). Hypoglycemia was identified as a withdrawal sign based on the SSRI studies. Tremors, hypotonia, tachycardia, rapid breathing, respiratory distress, and hypertonia were identified as withdrawal signs based on the SSRI/venlafaxine studies. The present work provides a framework for the identification of neonatal SSRI withdrawal syndrome. Tapering and discontinuation of antidepressant drugs before and during the early phase of pregnancy are worth attempting to prevent the occurrence of this syndrome.


Stigma and suicide warning signs.
The current study explored the relationship between stigma and suicide warning signs using a case vignette methodology. Three comparable vignettes were used varying only the essential warning signs, including heart attack, suicidality without specific mention of suicidal thinking, and suicidality with specific mention of suicidal thoughts and associated intent to die. After reading the vignette, participants responded to questions gauging urgency of response, along with their appraisal of the situation across six domains including: seriousness, time (how quickly should they respond), comfort 1 (how comfortable they were with the situation in general), sureness (how sure they were in their response), comfort 2 (how comfortable they were in implementing their response), and hopefulness (how hopeful they were that their response would be helpful). Consistent with study hypotheses, results indicated that participants were significantly less comfortable, less sure, and less hopeful when responding to a suicidal crisis when compared to a heart attack. In addition, participants were significantly less likely to access emergency services for a seriously suicidal individual in comparison to someone suffering a heart attack, instead choosing to talk with family and friends first. The potential moderating effects of family and individual history of psychiatric illness and treatment, along with current individual psychological symptoms, were also explored and discussed, with no significant impact uncovered. The importance of more targeted efforts to train individuals to not just recognize suicide warning signs, but on how to specifically respond, is emphasized.


SIMPLE: assessment of non-point phosphorus pollution from agricultural land to surface waters by means of a new methodology.
In the past, environmental Phosphorus (P) parameters like soil P indices have been used to catogorize the potential risk of P losses from agricultural land. In order to assess the actual risk of P pollution of groundwater and surface waters, dynamic process oriented soil and water quality models have been frequently used. Recently, an approximating model for phosphorus, called SIMPLE, has been developed. This model approximates the output from a complex dynamic water quality model. The approximating model is called a metamodel. This simple P-model proves to be a powerful tool for quick assessment of the risk of P pollution from agricultural land to surface waters.


Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation.
Traumatic brain injury (TBI), a complicated form of brain damage, is a major cause of mortality in adults. Following mechanical and structural primary insults, a battery of secondary insults, including neurotransmitter-mediated cytotoxicity, dysregulation of calcium and macromolecule homeostasis, and increased oxidative stress, exacerbate brain injury and functional deficits. Although stem cell therapy is considered to be an alternative treatment for brain injuries, such as TBI and stroke, many obstacles remain. In particular, the time window for TBI treatment with either drugs or stem cells and their efficacy is still vague. Human placenta-derived mesenchymal stem cells (hpMSCs) have received extensive attention in stem cell therapy because they can be acquired in large numbers without ethical issues and because of their immune-modulating capacity and effectiveness in several diseases, such as Alzheimer's disease and stroke. Here, we tested the feasibility of hpMSCs for TBI treatment with an animal model and attempted to identify appropriate time points for cell treatments. Double injections at 4 and 24 h post-injury significantly reduced the infarct size and suppressed astrocyte and microglial activation around the injury. With reduced damage, double-injected mice showed enhanced anti-inflammatory- and TNF-α receptor 2 (TNFR2)-associated survival signals and suppressed pro-inflammatory and oxidative responses. In addition, double-treated TBI mice displayed restored sensory motor functions and reduced neurotoxic Aβ42 plaque formation around the damaged areas. In this study, we showed the extended therapeutic potentials of hpMSCs and concluded that treatment within an appropriate time window is critical for TBI recovery.


Relationship of hydrolase activities to epithelial cell turnover in distal colonic mucosa of normal rats.
The relationships between changes induced by diet in colonic epithelial kinetics and in the activities of brush border hydrolases are poorly defined. The aims of this study are to define these relationships, as changes in kinetics would be expected to influence differentiation, and to determine whether the type of ingested dietary indigestible carbohydrates influences hydrolase activities. Groups of eight rats were fed a low fibre diet +/- supplements of different types of indigestible carbohydrates for 4 weeks. Alkaline phosphatase (ALP) and dipeptidyl peptidase IV (DPPIV) activities and epithelial kinetics were measured in distal colonic mucosa. Median ALP activities correlated positively and DPPIV activity negatively with the median proportion of cells entering metaphase (r = 0.58 and -0.58, respectively; P < 0.05) and number of metaphase arrests per crypt column across the diets (r = 0.59 and 0.58, respectively; P < 0.05). Stepwise regression analysis showed that both hydrolases independently predicted these kinetic indices (R2 > 63% for each). Mucosal ALP activities were markedly elevated during consumption of raw potato starch, guar gum and methylcellulose, while only potato starch caused a significant elevation of DPPIV activities. The type of indigestible carbohydrate in the diet influences colonic mucosal hydrolase activities. The opposite relationship between kinetics and each of the two hydrolases indicates that these hydrolases do not reflect the same event; dipeptidyl peptidase IV might relate to differentiation status while ALP could also be influenced by epithelial irritation due to changes in luminal conditions.


In vivo behavior of three different injectable hydraulic calcium phosphate cements.
Two dicalcium phosphate dihydrate (DCPD) hydraulic cements and one apatite hydraulic cement were implanted in epiphyseal and metaphyseal, cylindrical bone defects of sheep. The in vivo study was performed to assess the biocompatibility of the DCPD cements, using the apatite cement as control. After time periods of 2, 4 and 6 months the cement samples were clinically and histologically evaluated. Histomorphometrically the amount of new bone formation, fibrous tissue and the area of remaining cement were measured over time. In all specimens, no signs of inflammation were detectable either macroscopically or microscopically. All cements were replaced by different amounts of new bone. The two DCPD-cements showed the highest new bone formation and least cement remnants at 6 months, whereas the apatite was almost unchanged over all time periods.


Personal assistance for older adults (65+) without dementia.
There is a high prevalence of impairments among people 65+, and the elderly population is increasing in the West. Many countries offer personal assistance, individualised support for people living in the community by a paid assistant other than a healthcare professional for at least 20 hours per week. To assess the effectiveness of personal assistance for older adults with impairments, and the impacts of personal assistance on others, compared to other interventions. Electronic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Dissertation Abstracts International and a variety of specialist Swedish databases were searched from 1980 to June 2005; reference lists were checked; 345 experts, organisations, government bodies and charities were contacted in an attempt to locate relevant research. This review included older adults (65+) living in the community who require assistance to perform tasks of daily living (e.g., bathing and eating) and participate in normal activities due to permanent impairments. Controlled studies of personal assistance in which participants were prospectively assigned to study groups and in which control group outcomes were measured concurrently with intervention group outcomes were included. Titles and abstracts were examined by two reviewers. Outcomes data were extracted. Because they made different comparisons, studies were not combined for meta-analyses. Studies were assessed for the possibility of bias. Results and potential sources of bias are presented for included studies. Four studies involving 1642 participants made three eligible comparisons: (i) personal assistance versus usual care, (ii) personal assistance versus nursing homes, and (iii) personal assistance versus 'cluster care'. One was an RCT, three were non-randomised. Personal assistance was generally preferred over other services; however, some people prefer other models of care. This review indicates that personal assistance probably has some benefits for some recipients and caregivers. Paid assistance probably substitutes for informal care and may cost government more than alternatives; however, the total costs to recipients and society are currently unknown. Research in this field is limited. Personal assistance is expensive and difficult to organise, especially in places that do not already have services in place. When implementing new programmes, recipients could be randomly assigned to different forms of assistance. While advocates may support personal assistance for myriad reasons, this review demonstrates that further studies are required to determine which models of personal assistance are most effective and efficient.


The Effect of Isotonic Saline Nasal Lavages in Improving Symptoms in SARS-CoV-2 Infection: A Case-Control Study.
Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mainly colonizes nasopharynx. In upper airways acute infections, e.g., the common cold, saline nasal irrigations have a significant efficacy in reducing symptoms. The present study aimed to test the efficacy of nasal lavages in upper airways symptoms of Coronavirus Disease 2019 (COVID-19). Methods: A series of consecutive adult subjects who tested positive for SARS-CoV-2 from December 2020 to February 2021 performed daily nasal lavages with saline solution (Lavonase®-Purling, Lugo di Romagna, Italy) for 12 days, starting on the day after the SARS-CoV-2 positive swab. A control group included a historical series of patients who were infected in February-March 2020 and who did not perform lavages. An ad hoc questionnaire regarding symptoms was administered to each subjects at base-line and 10 days after diagnosis (i.e., on the same day of the control swab) in both cases and controls. Results: A total of 140 subjects were enrolled. 68 participants in the treatment group and 72 in the control group were included. 90% of respondents declared the lavages were simple to use and 70% declared they were satisfied. Symptoms of blocked nose, runny nose, or sneezing decreased by an average of 24.7% after the treatment. Blocked nose and sneezing increased in the same period of time in the control group. Ears and eyes symptoms, anosmia/ageusia symptoms, and infection duration (10.53 days in the treatment group and 10.48 days in the control group) didn't vary significantly among the two groups. Conclusion: Nasal lavages resulted to significantly decrease nasal symptoms in newly diagnosed SARS-CoV-2 patients. These devices proved to be well-tolerated and easy to be used. Further studies on a larger number of subjects are needed in order to possibly confirm these preliminary results.


Comparison of amino acid digestibility in full-fat soybean, two soybean meals, and peanut flour between broiler chickens and growing pigs.
The aim of this study was to determine the apparent ileal digestibility (AID) and the standardized ileal digestibility (SID) of CP and AA in full-fat soybean (FFSB), solvent-extracted soybean meal containing 430 g/kg CP (SBM-43), solvent-extracted soybean meal containing 470 g/kg CP (SBM-47), and peanut flour (PNF) fed to broiler chickens and pigs and to compare the digestibility of CP and AA between broiler chickens and pigs. Four diets were prepared to contain FFSB, SBM-43, SBM-47, and PNF as the sole source of N. A N-free diet was formulated to estimate the basal ileal endogenous losses of CP and AA for broiler chickens and pigs. In Exp. 1, a total of four hundred sixteen 21-d-old male broiler chickens (922.1 ± 79.9 g initial BW) were assigned to 5 experimental diets in a randomized complete block design with BW as a blocking factor. After 5 d of adaptation, ileal digesta samples were collected after birds were euthanized by CO asphyxiation. In Exp. 2, twenty barrows (62.0 ± 6.9 kg initial BW) surgically fitted with T-cannulas at the distal ileum were allotted to 5 experimental diets with 2 consecutive 7-d experimental periods. After 5 d of adaptation, ileal digesta samples were collected at d 6 and 7. For statistical analysis, treatments were considered a 2 × 4 factorial arrangement with effects of species and experimental diets (Exp. 1 vs. Exp. 2). There were no interactions between species and diets for the digestibility of CP and AA except for Cys ( < 0.01). The AID of CP and indispensable AA in pigs were greater ( < 0.01) than in broiler chickens. In both broiler chickens and pigs, the AID of CP and indispensable AA in SBM-47 were greater ( < 0.05) than in FFSB, and the AID of Lys in PNF was the least ( < 0.05) among ingredients. The SID of CP and indispensable AA in pigs were greater ( < 0.05) than in broiler chickens except for Trp. In both broiler chickens and pigs, the SID of Lys in PNF was the least ( < 0.05) among ingredients. In broiler chickens, the SID of CP, Ile, Leu, Thr, Trp, and Val in FFSB were less ( < 0.05) than that in SBM-43, SBM-47, and PNF. In pigs, the SID of Arg, Ile, Leu, Met, Phe, and Val in FFSB were less ( < 0.05) than in SBM-43, SBM-47, and PNF. In conclusion, the digestibility of CP and most AA were less in broiler chickens than in pigs, but the pattern of differences in the AA digestibility among ingredients was similar between broiler chickens and pigs.


Injury morbidity in 18-64-year-olds: impact and risk factors.
Non-fatal injury is an important public health problem but is thought to be difficult to quantify. This study aimed to estimate the extent of disability attributable to injury in the working age population, and its impact on quality of life, as well as identifying factors associated with an increased risk of disabling and non-disabling injury. Secondary analysis was carried out of data obtained from a postal questionnaire survey of 8889 18-64-year-olds randomly selected from computerized general practitioner records in Oxfordshire, Buckinghamshire, Berkshire and Northamptonshire. Sixteen per cent of survey respondents reported an injury requiring medical attention in the previous 12 months, 5 per cent reported an injury that had disabled them for more than 1 month, and a further 5 per cent a longstanding disability as a result of injury. The point prevalence of disability as a result of injury was estimated to be 6.4 per cent. SF-36 scores suggest that the quality of life of people reporting injury-related disability was markedly reduced. Social class is associated less with injury morbidity than with injury mortality. Sport was the commonest cause of all injuries, and of disabling injuries. There was a dose-response relationship between vigorous exercise and injury. Injury is a significant cause of disability in the working age population. It is potentially feasible to monitor injury-related disability in postal questionnaire surveys. Estimates of health gain to be achieved from participation in sport should take account of injury-related disability.


Liquid micro-lens array activated by selective electrowetting on lithium niobate substrates.
Lens effect was obtained in an open microfluidic system by using a thin layer of liquid on a polar electric crystal like LiNbO3. An array of liquid micro-lenses was generated by electrowetting effect in pyroelectric periodically poled crystals. Compared to conventional electrowetting devices, the pyroelectric effect allowed to have an electrode-less and circuit-less configuration. An interferometric technique was used to characterize the curvature of the micro-lenses and the corresponding results are presented and discussed. The preliminary results concerning the imaging capability of the micro-lens array are also reported.


Related Health Factors of Psychological Distress During the COVID-19 Pandemic in Spain.
Measures to prevent and contain the COVID-19 health crisis include population confinement, with the consequent isolation and interruption of their usual activities. The aim of the study is to analyse psychological distress during the COVID-19 pandemic. For this, a cross-sectional observational study with a sample of 4180 people over the age of 18 during quarantine was developed. Variables considered were sociodemographic variables, physical symptoms, health conditions, COVID-19 contact history and psychological adjustment. The data were collected through a self-developed questionnaire and the General Health Questionnaire (GHQ-12). Bivariate analyses were performed, including Chi-Squared test and Student's T-test. Predictive ability was calculated through logistic regression. Results obtained showed a high level of psychological distress (72.0%), with a higher percentage in women and people of lower middle age. Statistically significant differences were found in the variable working situation (χ² = 63.139, p ≤ 0.001, V = 0.123) and living with children under the age of 16 (χ² = 7.393, p = 0.007, V = 0.042). The predictive variables with the highest weight were sex (OR = 1.952, 95% IC = (1.667, 2.286)), presence of symptoms (OR = 1.130, 95% CI = (1.074, 1.190)), and having had close contact with an individual with confirmed COVID-19 (OR = 1.241, 95% CI = (1.026, 1.500)). These results could enrich prevention interventions in public health and, in particular, in mental health in similar pandemic situations.


Use of low-coverage, large-insert, short-read data for rapid and accurate generation of enhanced-quality draft Pseudomonas genome sequences.
Next-generation genomic technology has both greatly accelerated the pace of genome research as well as increased our reliance on draft genome sequences. While groups such as the Genomics Standards Consortium have made strong efforts to promote genome standards there is a still a general lack of uniformity among published draft genomes, leading to challenges for downstream comparative analyses. This lack of uniformity is a particular problem when using standard draft genomes that frequently have large numbers of low-quality sequencing tracts. Here we present a proposal for an "enhanced-quality draft" genome that identifies at least 95% of the coding sequences, thereby effectively providing a full accounting of the genic component of the genome. Enhanced-quality draft genomes are easily attainable through a combination of small- and large-insert next-generation, paired-end sequencing. We illustrate the generation of an enhanced-quality draft genome by re-sequencing the plant pathogenic bacterium Pseudomonas syringae pv. phaseolicola 1448A (Pph 1448A), which has a published, closed genome sequence of 5.93 Mbp. We use a combination of Illumina paired-end and mate-pair sequencing, and surprisingly find that de novo assemblies with 100x paired-end coverage and mate-pair sequencing with as low as low as 2-5x coverage are substantially better than assemblies based on higher coverage. The rapid and low-cost generation of large numbers of enhanced-quality draft genome sequences will be of particular value for microbial diagnostics and biosecurity, which rely on precise discrimination of potentially dangerous clones from closely related benign strains.


Injection site abscess due to Mycobacterium fortuitum: a case report.
Injection abscess is an iatrogenic infection occurring as an isolated case or as cluster outbreak. These infections occur due to contaminated injectables or lapse in sterilisation protocol. While pathogens such as Pseudomonas, Klebsiella, E. coli, and S. aureus are the usual causative agents, unusual organisms such as mycobacteria, particularly the rapidly growing non-tuberculous mycobacteria (NTM) may cause the abscess. The chances of overlooking these organisms is high unless an acid fast bacilli (AFB) smear and culture is done on all aspirated pus specimens. We report a case of a three year old child who presented with a gluteal abscess following an intramuscular infection with an unknown preparation.


Mortality from Selected Cancers among Brazilian Mechanics.
Mechanics are exposed to known human carcinogens. This study aimed to compare mortality from selected cancers between male mechanics and the general population of the South and Southeast regions of Brazil. Data on deaths, occurred between 2006-2017, among male mechanics and the general population, were obtained from the Mortality Information System. Occupations were classified using the Brazilian Classification of Occupations. Mortality Odds Ratio (MOR) and confidence intervals (95%) for selected cancers among mechanics, stratified by age (30-49, 50-69 years), race, and education compared to the general population, were estimated using logistic regression models. In general, mechanics showed higher mortality from oropharynx, hypopharynx, larynx, lung and bladder cancers, but lower mortality for all leukemias. Oropharynx and larynx cancer mortality risk was slightly higher among older mechanics, while hypopharynx cancer mortality was more noticeable among the youngest. Lower mortality from all leukemias was observed only among younger mechanics. Mortality by oropharynx and larynx cancers were higher among white mechanics. They were also the only ones to experience higher mortality by hypopharynx cancer, while lung cancer mortality were increased only among non-white ones. Mechanics of all educational levels were more likely to die by the oropharynx cancer. Those with 1-7 and 8 or more years of schooling also showed excess of death by the cancers of larynx and all leukemias. Significantly higher mortality by pancreas cancer was only observed among mechanics with no education, while those with 1-7 years of schooling showed higher risk to die by lung and bladder cancers. Those with 8 or more years of schooling show increased mortality risk for hypopharynx cancer. Increased mortality risk for myeloid leukemia was only observed when stratified by region of residence. Results of our study suggest a positive association between mechanic occupation and some specific cancers.<br />.


Activation of Conjunctiva-Associated Lymphoid Tissue in Patients With Infectious Keratitis Using In Vivo Confocal Microscopy.
We aimed to evaluate activation of conjunctiva-associated lymphoid tissue (CALT) in patients with keratitis using in vivo confocal microscopy (IVCM) and conjunctival impression cytology (CIC). In addition to anterior segment photography and corneal fluorescein staining, IVCM revealed the palpebral conjunctiva in all subjects, and CIC and immunofluorescence staining were performed. Diffuse lymphoid tissue cell density in the eyes of patients with keratitis was significantly greater compared with healthy volunteers (P < 0.001). Similar trends were found in perifollicular lymphocyte density (P < 0.001), follicular density (P = 0.029), follicular center reflection intensity (P = 0.011), and follicular area (P < 0.001). Immunofluorescence staining showed that the proportions of CD4+ (61.7% ± 8.0% vs. 17.3% ± 10.2%, respectively, P < 0.001) and CD8+ (46.9% ± 10.0% vs. 19.6% ± 11.5%, respectively, P < 0.001) cells in patients with keratitis was greater compared with healthy volunteers. Interestingly, we also observed changes in the contralateral eye in subjects with keratitis. Our research suggests that CALT, as an ocular immune structure, is activated and plays an important role in the pathogenesis of keratitis. This has been overlooked previously. CALT is also active in the contralateral eye of subjects with keratitis.


Photobiomodulation in Neuroscience: A Summary of Personal Experience.
This review summarizes personal experience with laser photobiomodulation and its potentials for the treatment of peripheral and central nerve system injuries. Laser photobiomodulation was shown to induce nerve cell activation, have a positive effect on metabolism of the nerve cells, and to stimulate nerve sprouting processes. Studies investigating the effects of laser photobiomodulation on injured peripheral nerves in rats reported immediate protective effects which increase the functional activity of the nerve, decrease or prevent scar tissue formation at the injured site, prevent or decrease degeneration in corresponding motor neurons of the spinal cord, and significantly increase axonal growth and myelinization. A direct application of laser on the spinal cord had a positive impact on the corresponding injured peripheral nerve and promoted recovery. A 780-nm laser phototherapy was applied following peripheral nerve reconstruction using a guiding nerve tube. Results showed myelinated axons crossing through the nerve tube and the continuation of axonal sprouting through the tube toward the distal part of the nerve. In a double-blind, placebo-controlled randomized pilot clinical trial in patients with incomplete stable long-term peripheral nerve injury (PNI), 780-nm laser irradiation progressively improved peripheral nerve function and led to substantial functional recovery. Muscle atrophy represents a major challenge in restorative medicine. Laser phototherapy was shown to increase biochemical activity and improve morphological recovery in muscle and, thus, could have a direct therapeutic application, especially during progressive muscle atrophy resulting from PNI. The effectiveness of composite implants of cultured embryonal nerve cells and the role of laser irradiation on regeneration and repair of the completely transected rat spinal cord were examined. Results suggested that laser photobiomodulation treatment accelerates the axonal growth. The significance of the performed experimental and clinical studies is in the provision of new laser technology in field of cell therapy and its therapeutic value for peripheral nerve and spinal cord injuries. Additional well-designed clinical studies are needed to evaluate the effectiveness and role of laser photobiomodulation treatment in a clinical setting.


Impact of a 2-year trial of nutritional ketosis on indices of cardiovascular disease risk in patients with type 2 diabetes.
We have previously reported that in patients with type 2 diabetes (T2D) consumption of a very low carbohydrate diet capable of inducing nutritional ketosis over 2 years (continuous care intervention, CCI) resulted in improved body weight, glycemic control, and multiple risk factors for cardiovascular disease (CVD) with the exception of an increase in low density lipoprotein cholesterol (LDL-C). In the present study, we report the impact of this intervention on markers of risk for atherosclerotic cardiovascular disease (CVD), with a focus on lipoprotein subfraction particle concentrations as well as carotid-artery intima-media thickness (CIMT). Analyses were performed in patients with T2D who completed 2 years of this study (CCI; n = 194; usual care (UC): n = 68). Lipoprotein subfraction particle concentrations were measured by ion mobility at baseline, 1, and 2 years and CIMT was measured at baseline and 2 years. Principal component analysis (PCA) was used to assess changes in independent clusters of lipoprotein particles. At 2 years, CCI resulted in a 23% decrease of small LDL IIIb and a 29% increase of large LDL I with no change in total LDL particle concentration or ApoB. The change in proportion of smaller and larger LDL was reflected by reversal of the small LDL subclass phenotype B in a high proportion of CCI participants (48.1%) and a shift in the principal component (PC) representing the atherogenic lipoprotein phenotype characteristic of T2D from a major to a secondary component of the total variance. The increase in LDL-C in the CCI group was mainly attributed to larger cholesterol-enriched LDL particles. CIMT showed no change in either the CCI or UC group. Consumption of a very low carbohydrate diet with nutritional ketosis for 2 years in patients with type 2 diabetes lowered levels of small LDL particles that are commonly increased in diabetic dyslipidemia and are a marker for heightened CVD risk. A corresponding increase in concentrations of larger LDL particles was responsible for higher levels of plasma LDL-C. The lack of increase in total LDL particles, ApoB, and in progression of CIMT, provide supporting evidence that this dietary intervention did not adversely affect risk of CVD.


Burden of type 2 diabetes attributed to lower educational levels in Sweden.
Type 2 diabetes is associated with low socioeconomic position (SEP) in high-income countries. Despite the important role of SEP in the development of many diseases, no socioeconomic indicator was included in the Comparative Risk Assessment (CRA) module of the Global Burden of Disease study. We therefore aimed to illustrate an example by estimating the burden of type 2 diabetes in Sweden attributed to lower educational levels as a measure of SEP using the methods applied in the CRA. To include lower educational levels as a risk factor for type 2 diabetes, we pooled relevant international data from a recent systematic review to measure the association between type 2 diabetes incidence and lower educational levels. We also collected data on the distribution of educational levels in the Swedish population using comparable criteria for educational levels as identified in the international literature. Population attributable fractions (PAF) were estimated and applied to the burden of diabetes estimates from the Swedish burden of disease database for men and women in the separate age groups (30-44, 45-59, 60-69, 70-79, and 80+ years). The PAF estimates showed that 17.2% of the diabetes burden in men and 20.1% of the burden in women were attributed to lower educational levels in Sweden when combining all age groups. The burden was, however, most pronounced in the older age groups (70-79 and 80+), where lower educational levels contributed to 22.5% to 24.5% of the diabetes burden in men and 27.8% to 32.6% in women. There is a considerable burden of type 2 diabetes attributed to lower educational levels in Sweden, and socioeconomic indicators should be considered to be incorporated in the CRA.


Working memory and the organization of brain systems.
Working memory has historically been viewed as an active maintenance process that is independent of long-term memory and independent of the medial temporal lobe. However, impaired performance across brief time intervals has sometimes been described in amnesic patients with medial temporal lobe damage. These findings raise a fundamental question about how to know when performance depends on working memory and when the capacity for working memory has been exceeded and performance depends on long-term memory. We describe a method for identifying working memory independently of patient performance. We compared patients with medial temporal lobe damage to controls who were given either distraction or no distraction between study and test. In four experiments, we found concordance between the performance of patients and the effect of distraction on controls. The patients were impaired on tasks in which distraction had minimal effect on control performance, and the patients were intact on tasks in which distraction disrupted control performance. We suggest that the patients were impaired when the task minimally depended on working memory (and instead depended substantially on long-term memory), and they performed well when the task depended substantially on working memory. These findings support the conclusion that working memory (active maintenance) is intact after medial temporal lobe damage.


A combination of oxygenation and driving pressure can provide valuable information in predicting the risk of mortality in ARDS patients.
Acute respiratory distress syndrome (ARDS) is a common life-threatening condition in critically ill patients. Itis also an important public health issue because it can cause substantial mortality and health care burden worldwide. The objective of this study was to investigate therisk factors that impact ARDS mortality in a medical center in Taiwan. This was a single center, observational study thatretrospectively analyzed data from adults in 6 intensive care units (ICUs) at Taichung Veterans General Hospital in Taiwan from 1st October, 2018to30th September, 2019. Patients needing invasive mechanical ventilation and meeting the Berlin definition criteria were included for analysis. A total of 1,778 subjects were screened in 6 adult ICUs and 370 patients fulfilled the criteria of ARDS in the first 24 hours of the ICU admission. Among these patients, the prevalenceof ARDS was 20.8% and the overall hospital mortality rate was 42.2%. The mortality rates of mild, moderate and severe ARDS were 35.9%, 43.9% and 46.5%, respectively. In a multivariate logistic regression model, combination of driving pressure (DP) > 14cmH2O and oxygenation (P/F ratio)≤150 was an independent predictor of mortality (OR2.497, 95% CI 1.201-5.191, p = 0.014). Patients with worse oxygenation and a higher driving pressure had the highest hospital mortality rate(p<0.0001). ARDS is common in ICUs and the mortality rate remains high. Combining oxygenation and respiratory mechanics may better predict the outcomes of these ARDS patients.


New 4-point pharmacophore method for molecular similarity and diversity applications: overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures.
A new 4-point pharmacophore method for molecular similarity and diversity that rapidly calculates all potential pharmacophores/pharmacophoric shapes for a molecule or a protein site is described. The method, an extension to the ChemDiverse/Chem-X software (Oxford Molecular, Oxford, England), has also been customized to enable a new internally referenced measure of pharmacophore diversity. The "privileged" substructure concept for the design of high-affinity ligands is presented, and an example of this new method is described for the design of combinatorial libraries for 7-transmembrane G-protein-coupled receptor targets, where "privileged" substructures are used as special features to internally reference the pharmacophoric shapes. Up to 7 features and 15 distance ranges are considered, giving up to 350 million potential 4-point 3D pharmacophores/molecule. The resultant pharmacophore "key" ("fingerprint") serves as a powerful measure for diversity or similarity, calculable for both a ligand and a protein site, and provides a consistent frame of reference for comparing molecules, sets of molecules, and protein sites. Explicit "on-the-fly" conformational sampling is performed for a molecule to enable the calculation of all geometries accessible for all combinations of four features (i.e., 4-point pharmacophores) at any desired sampling resolution. For a protein site, complementary site points to groups displayed in the site are generated and all combinations of four site points are considered. In this paper we report (i) the details of our customized implementation of the method and its modification to systematically measure 4-point pharmacophores relative to a "special" substructure of interest present in the molecules under study; (ii) comparisons of 3- and 4-point pharmacophore methods, highlighting the much increased resolution of the 4-point method; (iii) applications of the 4-point potential pharmacophore descriptors as a new measure of molecular similarity and diversity and for the design of focused/biased combinatorial libraries.


Role of ERCP in the era of laparoscopic cholecystectomy for the evaluation of choledocholithiasis in sickle cell anemia.
To evaluate the role of endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis in patients with sickle cell anemia (SCA) in the era of laparoscopic cholecystectomy (LC). Two hundred and twenty four patients (144 male, 80 female; mean age, 22.4 years; range, 5-70 years) with SCA underwent ERCP as part of their evaluation for cholestatic jaundice (CJ). The indications for ERCP were: CJ only in 97, CJ and dilated bile ducts on ultrasound in 103, and CJ and common bile duct (CBD) stones on ultrasound in 42. In total, CBD stones were found in 88 (39.3%) patients and there was evidence of recent stone passage in 16. Fifteen were post-LC patients. These had endoscopic sphincterotomy and stone extraction. The remaining 73 had endoscopic sphincterotomy and stone extraction followed by LC without an intraoperative cholangiogram. In patients with SCA and cholelithiasis, ERCP is valuable whether preoperative or postoperative, and in none was there a need to perform intraoperative cholangiography. Sequential endoscopic sphincterotomy and stone extraction followed by LC is beneficial in these patients. Endoscopic sphincterotomy may also prove to be useful in these patients as it may prevent the future development of biliary sludge and bile duct stones.


Coherent detection techniques in optical imaging of tissues.
To form optical images from the transmitted or reflected light that is multiply scattered inside biological tissue, several detection techniques that extract the least-scattered photons or path-resolved photons have been developed. This paper reviews the coherent detection techniques. Emphasis is put on coherent detection imaging methods based on optical heterodyning, whose attractive features include quantum-noise-limited sensitivity, wide dynamic range, and excellent directionality and selectivity. Coherent detection methods have been implemented to achieve laser computed tomography and micrometre-resolution cross-sectional images in both in vivo and in vitro biological systems. Imaging works by ourselves and others are described, and an experimental study on coherent photon migration through highly scattering media is described to aid the understanding of the coherent detection method in selectively detecting the signal-carrying photons.


Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells.
Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.


Bringing science to medicine: an interview with Larry Weed, inventor of the problem-oriented medical record.
Larry Weed, MD is widely known as the father of the problem-oriented medical record and inventor of the now-ubiquitous SOAP (subjective/objective/assessment/plan) note, for developing an electronic health record system (Problem-Oriented Medical Information System, PROMIS), and for founding a company (since acquired), which developed problem-knowledge couplers. However, Dr Weed's vision for medicine goes far beyond software--over the course of his storied career, he has relentlessly sought to bring the scientific method to medical practice and, where necessary, to point out shortcomings in the system and advocate for change. In this oral history, Dr Weed describes, in his own words, the arcs of his long career and the work that remains to be done.


Use of sildenafil citrate in cases of intrauterine growth restriction (IUGR); a prospective trial.
Intrauterine growth restriction (IUGR) is one of the most serious complications of pregnancy. Up to date, there is no evidence of achieving antenatal treatment of IUGR with abnormal placentation. Although, Sildenafil citrate has shown promising results, there are no firm conclusion till now. The aim of our study is to evaluate the use of Sildenafil citrate in the treatment of IUGR cases associated with impaired placental circulation. This was a prospective non-randomized study conducted at Mansoura university hospitals starting from March 2016 till October 2017. The studied population included singleton pregnancy and suffering from IUGR associated with impaired placental circulation. This study included 50 pregnant women. Cases were divided into two groups. The first group received sildenafil citrate and the second control group did not receive sildenafil citrate. After 4 weeks after the 1st dose of Sildenafil significant decrease in umbilical artery Doppler indices. There was a statistically significant difference in the mean birth weight at delivery and neonatal admission to the newborn nursery in sildenafil group. sildenafil citrate treatment may present a new hope towards better perinatal outcomes for pregnancies complicated by IUGR and impaired placental circulation that may help to decrease neonatal admission to the newborn nursery.


Joint international consensus statement for ending stigma of obesity.
People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.


Impact of spinopelvic alignment on decision making in deformity surgery in adults: A review.
Sagittal spinal misalignment (SSM) is an established cause of pain and disability. Treating physicians must be familiar with the radiographic findings consistent with SSM. Additionally, the restoration or maintenance of physiological sagittal spinal alignment after reconstructive spinal procedures is imperative to achieve good clinical outcomes. The C-7 plumb line (sagittal vertical axis) has traditionally been used to evaluate sagittal spinal alignment; however, recent data indicate that the measurement of spinopelvic parameters provides a more comprehensive assessment of sagittal spinal alignment. In this review the authors describe the proper analysis of spinopelvic alignment for surgical planning. Online videos supplement the text to better illustrate the key concepts.


Rational design of a structural and functional nitric oxide reductase.
Protein design provides a rigorous test of our knowledge about proteins and allows the creation of novel enzymes for biotechnological applications. Whereas progress has been made in designing proteins that mimic native proteins structurally, it is more difficult to design functional proteins. In comparison to recent successes in designing non-metalloproteins, it is even more challenging to rationally design metalloproteins that reproduce both the structure and function of native metalloenzymes. This is because protein metal-binding sites are much more varied than non-metal-containing sites, in terms of different metal ion oxidation states, preferred geometry and metal ion ligand donor sets. Because of their variability, it has been difficult to predict metal-binding site properties in silico, as many of the parameters, such as force fields, are ill-defined. Therefore, the successful design of a structural and functional metalloprotein would greatly advance the field of protein design and our understanding of enzymes. Here we report a successful, rational design of a structural and functional model of a metalloprotein, nitric oxide reductase (NOR), by introducing three histidines and one glutamate, predicted as ligands in the active site of NOR, into the distal pocket of myoglobin. A crystal structure of the designed protein confirms that the minimized computer model contains a haem/non-haem Fe(B) centre that is remarkably similar to that in the crystal structure. This designed protein also exhibits NO reduction activity, and so models both the structure and function of NOR, offering insight that the active site glutamate is required for both iron binding and activity. These results show that structural and functional metalloproteins can be rationally designed in silico.


Do Municipal Contexts Matter for Adolescent Mental Health? A Within-Municipality Analysis of Nationwide Norwegian Survey Data Across Six Years.
Despite growing concerns about substantial socio-economic differences between districts in many developed nations, limited attention has been paid to how adolescent mental health may be shaped by district characteristics. A few studies have shown that adolescent mental health is related to contextual factors such as district socio-economic status, neighborhood disorder, and quality of infrastructure. However, prior estimates may be an artifact of unmeasured differences between districts. To address these concerns, we used data from the nationwide Norwegian Ungdata surveys (N = 278,764), conducted across the years 2014 to 2019. We applied three-level hierarchical linear models to examine within-municipality associations between municipal factors and adolescent mental health in the domains of internalizing problems (i.e., depressive symptoms), externalizing problems (i.e., behavioral problems), and well-being (i.e., self-esteem), thereby accounting for all time-invariant municipality-level confounders. Our results showed that municipal-level safety, infrastructure, and youth culture are associated with adolescent mental health problems. Further, cross-level interaction models indicated gender-specific associations, with stronger associations of municipality infrastructure and community belongingness with increased self-esteem and reduced delinquent behaviors among girls than boys. Our findings highlight that municipality-level interventions may be a feasible strategy for adolescent mental health, even in a society characterized by low inequality and high redistribution.


Trends in Utilization of Total and Unicompartmental Knee Arthroplasty in the United States.
Total knee replacement (TKR) and unicompartmental knee replacement (UKR) are successful procedures for patients with knee arthritis. While strict criteria were proposed early on for UKR, some surgeons have expanded these indications to include younger and heavier patients. The purpose of this study is to analyze trends in usage of TKR and UKR in the United States. This retrospective study analyzed an insurance administrative dataset. Patients who underwent primary TKR and UKR were identified via current procedural terminology codes. Information on incidence, obesity, use of computer navigation, and surgical setting were collected. We analyzed 7,194 UKRs and 128,849 TKRs performed from 2007 to 2016. Prevalence of obesity in both groups increased over the study period. Utilization of computer navigation increased for UKR but declined for TKR. The rate of outpatient procedures significantly increased for UKR but remained constant for TKR. Both TKR and UKR are being performed at increasing rates and on heavier patients. The use of computer navigation and outpatient surgical setting is increasing for UKR but not for TKR. Knowledge of these trends is important for surgeons and policy-makers to help inform surgical indications and resource allocation.


Low grade serous ovarian carcinoma: identifying variations in practice patterns.
Low grade serous ovarian carcinoma is a rare subtype of ovarian cancer with an indolent and chemorefractory course. As such, treatment strategies among practitioners are not uniformly known. The primary objective of this study was to identify differences in practice patterns among physicians who treat low grade serous carcinoma. A de novo survey was distributed to members of the Society of Gynecologic Oncology. Questions about demographics, management of primary and recurrent disease, and use of consolidation therapy were included. Statistical analyses were performed using χ2 and Fisher's exact tests. 194 gynecologic oncologists completed the survey. Approximately two-thirds of respondents practiced in a university based setting and treated a high volume of ovarian cancers, including low grade serous carcinoma. 82% recommended somatic testing during treatment and 84% routinely sent patients for genetic counseling. Treatment preferences for primary disease varied by debulking status. 48% of practitioners used hormone antagonism as consolidation after primary treatment. Secondary cytoreduction was preferred for patients with platinum sensitive recurrence and a long disease free interval following primary treatment (P<0.001). Hormone antagonism was the preferred treatment for the first platinum resistant recurrence (54%), while a BRAF inhibitor was the preferred agent in platinum resistant recurrence in the presence of a known BRAF mutation (56%). There was significant variation in the preferred management of low grade serous carcinoma among practitioners. Further efforts to improve knowledge of this disease, identify optimal treatment modalities, and provide guidelines for management should be encouraged.


El Niño and human health.
The El Niño-Southern Oscillation (ENSO) is the best known example of quasi-periodic natural climate variability on the interannual time scale. It comprises changes in sea temperature in the Pacific Ocean (El Niño) and changes in atmospheric pressure across the Pacific Basin (the Southern Oscillation), together with resultant effects on world weather. El Niño events occur at intervals of 2-7 years. In certain countries around the Pacific and beyond, El Niño is associated with extreme weather conditions that can cause floods and drought. Globally it is linked to an increased impact of natural disasters. There is evidence that ENSO is associated with a heightened risk of certain vector-borne diseases in specific geographical areas where weather patterns are linked with the ENSO cycle and disease control is limited. This is particularly true for malaria, but associations are also suggested in respect of epidemics of other mosquito-borne and rodent-borne diseases that can be triggered by extreme weather conditions. Seasonal climate forecasts, predicting the likelihood of weather patterns several months in advance, can be used to provide early indicators of epidemic risk, particularly for malaria. Interdisciplinary research and cooperation are required in order to reduce vulnerability to climate variability and weather extremes.


The personal and social experiences of community-dwelling younger adults after stroke in Australia: a qualitative interview study.
To examine the personal and social experiences of younger adults after stroke. Qualitative study design involving in-depth semi-structured interviews and rigorous qualitative descriptive analysis informed by social constructionism. Nineteen younger stroke survivors aged 18 to 55 years at the time of their first-ever stroke. Participants were recruited from urban and rural settings across Australia. Interviews took place in a clinic room of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia), over an online conference platform or by telephone. Four main themes emerged from the discourses: (1) psycho-emotional experiences after young stroke; (2) losing pre-stroke life construct and relationships; (3) recovering and adapting after young stroke; and (4) invalidated by the old-age, physical concept of stroke. While these themes ran through the narratives of all participants, data analysis also drew out interesting variation between individual experiences. For many younger adults, stroke is an unexpected and devastating life event that profoundly diverts their biography and presents complex and continued challenges to fulfilling age-normative roles. While adaptation, resilience and post-traumatic growth are common, this study suggests that more bespoke support is needed for younger adults after stroke. Increasing public awareness of young stroke is also important, as is increased research attention to this problem.


Neurocognitive impairment in treatment-experienced adults living with HIV attending primary care clinics in Zimbabwe.
HIV affects the central nervous system resulting in HIV associated neurocognitive impairment (NCI) in approximately 50% of people living with HIV. It typically affects memory, learning, working memory, fine motor skills, speed of information processing, verbal fluency and executive functioning cognitive domains. NCI can affect adherence to antiretroviral therapy (ART), employability, driving ability and activities of daily living. NCI is not routinely screened for in Zimbabwe, and the burden is not known in this setting. The objectives of this study were: 1) To determine NCI prevalence using a comprehensive neuropsychological battery at two primary health care clinics in Harare; 2) To assess the pattern of cognitive impairment across cognitive domains using a gold standard neuropsychological (NP) battery in HIV-positive patients compared to HIV-negative controls. Inclusion criteria: 18 years or older; minimum 7 years education; no neurological or psychiatric disorders. HIV-positive participants were on ART for ≥3 months; HIV-negative participants had a confirmed HIV negative status in the past month. A comprehensive NP battery, functional assessments, demographic and medical history questionnaires were administered. The NP battery consisted of tests assessing memory, learning, working memory, fine motor skills, speed of information processing, verbal fluency and executive functioning. Two-hundred-and-thirty-one participants were recruited. Of those, 155 were HIV-positive (Female = 70%, Age M = 37.8; SD 11.2) and 76 HIV-negative (Female = 63%, Age M = 31.2; SD 9.9). HIV-positive participants were on ART for an average of 6 years. NCI was present in 49.7% HIV positive participants. Compared to HIV-negative participants, the HIV-positive group had significantly poorer scores in 5 out of 7 cognitive domains. A good level of education is negatively correlated with NCI. NCI prevalence in HIV-positive population Zimbabwe is consistent with global estimates. NCI persists in adults who are on ART. Routine assessment of NCI in adults attending primary care clinics using this adapted battery is therefore important so that they are identified early and are provided the necessary interventions.


Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.


Tinnitus, Use and Evaluation of Sound Therapy, Current Evidence and Area of Future Tinnitus Research.
Tinnitus is one of the otologic symptoms seen in persons with ear pathologies. It is defined as an acoustic sensation in the ear without a corresponding external acoustic stimulus. Tinnitus is said to be generated from the higher auditory centres because of reduced feedback from the peripheral or neural component but can be an outcome of irritation at different levels of the auditory system. Several treatment modalities have been tried in the management of tinnitus, either as a single treatment or as part of combination therapy. They range from lifestyle or dietary modification, medications, surgery, to Tinnitus Retraining Therapy (TRT), use of sound generating devices, hearing aids and cochlear implants. Current literature has shown that the prevalence of tinnitus is highly variable and reflects the difference in symptom criteria and patient selection for the various treatment modalities. This variability is also visible in the outcomes of cases where the various treatment modalities have been used. In the presence of an augmented hearing, the brain can focus on the meaningful sound generated externally while suppressing or even aborting the tinnitus. Future tinnitus research needs to apply the highest level of randomization and blinding, in line with the high subjectivity of tinnitus and the possibility of a response with control. The natural sequence of tinnitus is characterized by the conditioning or habituation and possible gradual attenuation of symptom, this implies that there is a limit to which the benefits observed was due to our intervention rather than a natural process of this symptom.


Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer.
Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance. Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors. VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER-positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor-positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status. Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor-positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.


The comparative effectiveness of ventricular shunt placement versus endoscopic third ventriculostomy for initial treatment of hydrocephalus in infants.
The purpose of this study was to compare the effectiveness of CSF diversion with endoscopic third ventriculostomy (ETV) versus shunt therapy in infants with hydrocephalus. The authors conducted a retrospective analysis of 5416 infants 1 year of age or younger with hydrocephalus (congenital or acquired) in whom CSF diversion was performed using either ETV or shunt placement at 41 children's hospitals between 2004 and 2009. Data were obtained from the Pediatric Health Information Systems database. Surgical failure was defined as the need for a repeat diversion operation within 1 year of initial surgery. The authors compared failure rates of ETV and shunt, as well as patient demographics and clinical characteristics, using hierarchical regression according to treatment group. During the period examined, 872 infants (16.1%) initially underwent ETV and 4544 (83.9%) underwent ventricular shunt placement. The median infant age was 37 days (IQR 11-122 days) for both ETV and shunt placement. More infants who underwent ETV rather than shunt placement were born prematurely (41.6% vs 23.9%, respectively; p < 0.01) and had intraventricular hemorrhage (45.4% vs 17.5%, respectively; p < 0.01). Higher operative failure rates at 1 year were observed in infants who underwent ETV as opposed to shunt surgery (64.5% vs 39.6%, respectively; OR 2.9 [95% CI 2.3-3.5], p < 0.01). After controlling for prematurity, intraventricular hemorrhage, and spina bifida, ETV remained associated with a higher risk of failure (OR 2.6 [95% CI 2.1-3.2]). In infants with hydrocephalus, a greater 1-year CSF diversion failure rate may occur after ETV compared with shunt placement. This risk is most significant for procedures performed within the first 90 days of life. Further investigation of the need for multiple reoperations, cost, and impact of surgeon and hospital experience is necessary to distinguish which treatment is more effective in the long term.


Baseline levels of soluble CD14 and CD16+56- natural killer cells are negatively associated with response to interferon/ribavirin therapy during HCV-HIV-1 coinfection.
Disease progression of human immunodeficiency virus type 1 (HIV-1) is associated with immune activation. Activation indices are higher during coinfection of hepatitis C virus (HCV) and HIV. The effect of immune activation on interferon α (IFN-α) therapy response is unknown. We evaluated soluble CD14 (sCD14) and natural killer (NK)-cell subsets at baseline, and during pegIFN-α2a/ribavirin therapy in HCV-HIV coinfection. The sCD14 level increased during therapy. Baseline sCD14 positively correlated with baseline HCV level and CD16(+)56(-) NK-cell frequency, and both sCD14 and CD16(+)56(-) NK cells correlated negatively with magnitude of HCV decline. IL28B genotype was associated with therapy response but not sCD14 or CD16(+)56(-) NK frequency. Markers of innate immune activation predict poor host response to IFN-α-based HCV therapy during HCV-HIV coinfection.


Breast cancer and other second neoplasms after childhood Hodgkin's disease.
Patients who survive Hodgkin's disease are at increased risk for second neoplasms. As survival times increase, solid tumors are emerging as a serious long-term complication. The Late Effects Study Group followed a cohort of 1380 children with Hodgkin's disease to determine the incidence of second neoplasms and the risk factors associated with them. In this cohort, there were 88 second neoplasms as compared with 4.4 expected in the general population (standardized incidence ratio, 18.1; 95 percent confidence interval, 14.3 to 22.3). The estimated actuarial incidence of any second neoplasm 15 years after the diagnosis of Hodgkin's disease was 7.0 percent (95 percent confidence interval, 5.2 to 8.8 percent); the incidence of solid tumors was 3.9 percent (95 percent confidence interval, 2.3 to 5.5 percent). Breast cancer was the most common solid tumor (standardized incidence ratio 75.3; 95 percent confidence interval, 44.9 to 118.4), with an estimated actuarial incidence in women that approached 35 percent (95 percent confidence interval, 17.4 to 52.6 percent) by 40 years of age. Older age (10 to 16 vs. <10 years) at the time of radiation treatment (relative risk, 1.9) and a higher dose (2000 to 4000 vs. <2000 cGy) of radiation (relative risk, 5.9) were associated with significantly increased risk of breast cancer. The estimated actuarial incidence of leukemia reached a plateau of 2.8 percent (95 percent confidence interval, 0.8 to 4.8 percent) 14 years after diagnosis. Treatment with alkylating agents, older age at the diagnosis of Hodgkin's disease, recurrence of Hodgkin's disease, and a late stage of disease at diagnosis were risk factors for leukemia. The risk of solid tumors, especially breast cancer, is high among women who were treated with radiation for childhood Hodgkin's disease. Systematic screening for breast cancer could be important in the health care of such women.


Diagnosis and treatment of osteoporosis.
Osteoporosis affects approximately 8 million women and 2 million men in the United States. The associated fractures are a common and preventable cause of morbidity and mortality in up to 50 percent of older women. The U.S. Preventive Services Task Force recommends using dual energy x-ray absorptiometry to screen all women 65 years and older and women 60 to 64 years of age who have increased fracture risk. Some organizations recommend considering screening in all men 70 years and older. For persons with osteoporosis diagnosed by dual energy x-ray absorptiometry or previous fragility fracture, effective first-line treatment consists of fall prevention, adequate intake of calcium (at least 1,200 mg per day) and vitamin D (at least 700 to 800 IU per day), and treatment with a bisphosphonate. Raloxifene, calcitonin, teriparatide, or hormone therapy maybe considered for certain subsets of patients.


Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review.
The clinical features in cases that have mutations in the microtubule-associated protein tau gene but lack prominent behavioral changes remain unclear. Here, we describe detailed clinical and pathological features of a case carrying the P301L tau mutation that showed only apathy until the middle stage of the course. The mother of this case was suspected to have mild cognitive decline at age 46. However, before she was fully examined, she had a subarachnoid hemorrhage at age 49 and died at age 53. An autopsy was not done. The proband of this pedigree, a 60-year-old right-handed Japanese man at the time of death, began to make mistakes at work at the age of 51 years. Until age 54, he showed only mild apathy with bradykinesia. Insight was well spared. Parkinsonism and echolalia developed at age 55, and pyramidal signs and oral tendency at age 57. Personality change, disinhibition, stereotypy, or semantic memory impairment was not found throughout the course. The final neurological diagnosis was unspecified dementia. Pathological examination demonstrated numerous round four-repeat tau-positive three-repeat tau-negative or perinuclear ring-like neuronal cytoplasmic inclusions with many ballooned neurons in the frontal and temporal cortices and hippocampus. Genetic analysis using frozen brain tissue demonstrated a P301L tau mutation. Among 31 previously reported cases bearing the P301L tau mutation for which the data regarding initial symptoms are available, one clinical case showed only apathy with depression in the early stage. Given these findings, clinicians should be aware that a clinical course characterized only by apathy for several years, which can be misdiagnosed as a psychiatric disorder, is one of the clinical presentations associated with P301L tau mutation.


Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.
In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.