In vivo analysis of an essential archaeal signal recognition particle in its native host.
The evolutionarily conserved signal recognition particle (SRP) plays an integral role in Sec-mediated cotranslational protein translocation and membrane protein insertion, as it has been shown to target nascent secretory and membrane proteins to the bacterial and eukaryotic translocation pores. However, little is known about its function in archaea, since characterization of the SRP in this domain of life has thus far been limited to in vitro reconstitution studies of heterologously expressed archaeal SRP components identified by sequence comparisons. In the present study, the genes encoding the SRP54, SRP19, and 7S RNA homologs (hv54h, hv19h, and hv7Sh, respectively) of the genetically and biochemically tractable archaeon Haloferax volcanii were cloned, providing the tools to analyze the SRP in its native host. As part of this analysis, an hv54h knockout strain was created. In vivo characterization of this strain revealed that the archaeal SRP is required for viability, suggesting that cotranslational protein translocation is an essential process in archaea. Furthermore, a method for the purification of this SRP employing nickel chromatography was developed in H. volcanii, allowing the successful copurification of (i) Hv7Sh with a histidine-tagged Hv54h, as well as (ii) Hv54h and Hv7Sh with a histidine-tagged Hv19h. These results provide the first in vivo evidence that these components interact in archaea. Such copurification studies will provide insight into the significance of the similarities and differences of the protein-targeting systems of the three domains of life, thereby increasing knowledge about the recognition of translocated proteins in general.


Flagellin delays spontaneous human neutrophil apoptosis.
Neutrophils are short-lived cells that rapidly undergo apoptosis. However, their survival can be regulated by signals from the environment. Flagellin, the primary component of the bacterial flagella, is known to induce neutrophil activation. In this study we examined the ability of flagellin to modulate neutrophil apoptosis. Neutrophils cultured for 12 and 24 h in the presence of flagellin from Salmonella typhimurium at concentrations found in pathological situations underwent a marked prevention of apoptosis. In contrast, Helicobacter pylori flagellin did not affect neutrophil survival, suggesting that Salmonella flagellin exerts the antiapoptotic effect by interacting with TLR5. The delaying in apoptosis mediated by Salmonella flagellin was coupled to higher expression levels of the antiapoptotic protein Mcl-1 and lower levels of activated caspase-3. Analysis of the signaling pathways indicated that Salmonella flagellin induced the activation of the p38 and ERK1/2 MAPK pathways as well as the PI3K/Akt pathway. Furthermore, it also stimulated IkappaBalpha degradation and the phosphorylation of the p65 subunit, suggesting that Salmonella flagellin also triggers NF-kappaB activation. Moreover, the pharmacological inhibition of ERK1/2 pathway and NF-kappaB activation partially prevented the antiapoptotic effects exerted by flagellin. Finally, the apoptotic delaying effect exerted by flagellin was also evidenced when neutrophils were cultured with whole heat-killed S. typhimurium. Both a wild-type and an aflagellate mutant S. typhimurium strain promoted neutrophil survival; however, when cultured in low bacteria/neutrophil ratios, the flagellate bacteria showed a higher capacity to inhibit neutrophil apoptosis, although both strains showed a similar ability to induce neutrophil activation. Taken together, our results indicate that flagellin delays neutrophil apoptosis by a mechanism partially dependent on the activation of ERK1/2 MAPK and NF-kappaB. The ability of flagellin to delay neutrophil apoptosis could contribute to perpetuate the inflammation during infections with flagellated bacteria.


Hydration of methemoglobin studied by in silico modeling and dielectric spectroscopy.
The hemoglobin concentration of 35 g/dl of human red blood cells is close to the solubility threshold. Using microwave dielectric spectroscopy, we have assessed the amount of water associated with hydration shells of methemoglobin as a function of its concentration in the presence or absence of ions. We estimated water-hemoglobin interactions to interpret the obtained data. Within the concentration range of 5-10 g/dl of methemoglobin, ions play an important role in defining the free-to-bound water ratio competing with hemoglobin to recruit water molecules for the hydration shell. At higher concentrations, hemoglobin is a major contributor to the recruitment of water to its hydration shell. Furthermore, the amount of bound water does not change as the hemoglobin concentration is increased from 15 to 30 g/dl, remaining at the level of ∼20% of the total intracellular water pool. The theoretical evaluation of the ratio of free and bound water for the hemoglobin concentration in the absence of ions corresponds with the experimental results and shows that the methemoglobin molecule binds about 1400 water molecules. These observations suggest that within the concentration range close to the physiological one, hemoglobin molecules are so close to each other that their hydration shells interact. In this case, the orientation of the hemoglobin molecules is most likely not stochastic, but rather supports partial neutralization of positive and negative charges at the protein surface. Furthermore, deformation of the red blood cell shape results in the rearrangement of these structures.


A Case with late onset of ambiguous genitalia.
Ambiguous genitalia is an uncommon situation that happens between 1 and 2 per every 1000 live births and falls under the umbrella diagnosis of disorders of sexual development. In this article, we report a case of male pseudohermaphroditism with ambiguous genitalia. The proband was a 12 yr old girl without any uterus or ovarian tissues. Karyotype of the case is 46, XY. Genes involved in sexual differentiation such as AR, SRD5A2, LH, LHR, FSH, 17 B HSD and SRY genes were sequenced in both directions. No mutations were found in these genes either. It seems advisable to be cautious in similar cases, and revise protocol for tracing the genes involved in the patients.


Quantitative study of the violation of kperpendicular factorization in hadroproduction of quarks at collider energies.
We demonstrate the violation of kperpendicular factorization for quark production in high energy hadronic collisions. This violation is quantified in the color glass condensate framework and studied as a function of the quark mass, the quark transverse momentum, and the saturation scale Q(s), which is a measure of large parton densities. At x values where parton densities are large but leading twist shadowing effects are still small, violations of kperpendicularkfactorization can be significant--especially for lighter quarks. At very small x, where leading twist shadowing is large, we show that violations of kperpendicular factorization are relatively weaker.


The measurement of digitoxin in human serum by radioimmunoassay.
A sensitive, specific, and relatively simple immunoassay permitting measurement of pharmacological levels of digitoxin in human serum has been developed. The assay involves binding of (125)I-labeled tyrosine-digitoxigenin (specific activity > 400 mc/mg) by rabbit antibody to digitoxin. Antibody-bound radioactivity is precipitated by addition of a second antibody (goat anti-rabbit gamma globulin), and precipitate radioactivity is measured. Unlabeled digitoxin can be determined by the extent to which it competes with (125)I-labeled digitoxigenin and thus reduces precipitation of radioactivity. Before the assay, unlabeled digitoxin is extracted from serum with chloroform, and the chloroform solution is evaporated to dryness. Quantitation is accomplished by reference to a standard curve in which known amounts of digitoxin are added to normal serum. As little as 1 mmug of digitoxin per ml of serum produces significant reduction in precipitate radioactivity. The sera of 5 patients were analyzed before and after digitalization. A highly significant reduction in precipitate counts in the postdigitalization sera was observed (P < 0.001). Serum digitalis levels were measured in 19 patients receiving no digitalis and in 19 patients taking digitoxin or digitalis leaf. Little of no digitalis-like activity was detected in control sera, whereas serum levels averaged 27 mmug/ml in those on digitalis (range 4-60 mmug/ml, P < 0.001). Patients judged clinically to show digitals toxicity in general had higher levels than those without signs of toxicity. Patients receiving digoxin had little or no detectable digitalis in their serum with this method. In addition to the assay itself, other potential uses of the antidigitalis antibody include treatment of digitalis toxicity and studies on the tissue localization of digitalis.


Evaluation of mesenchymal stem cells following implantation in alveolar sockets: a canine safety study.
The overall goal of this project was to evaluate culture-expanded bone-marrow-derived mesenchymal stem cells (MSCs) for alveolar bone repair in terms of safety and potential efficacy. MSCs isolated from bone marrow aspirations were culture-expanded and cryopreserved. Thawed cells were incubated with 3.2 x 5-mm hydroxyapatite/tricalcium phosphate (HA/TCP) cylinders in a closed system containing 5 x 10(7) cells/mL. Cells alone, cell-free constructs, or cell-loaded constructs were rinsed in saline and implanted in extraction sockets in the mandibular second and fourth premolar sites of 14 beagle dogs. Acute reactions were evaluated histologically after 7 or 21 days, and bone formation was examined after 49 days. Neither implanted MSC-related inflammation nor ectopic osteogenesis was observed. At 7 and 21 days, dil-labeled canine MSCs were found in more than 80% of the implant sites. Few canine MSCs were found in neighboring tissue. Mild inflammation present at 7 days diminished by 21 days. After 49 days, measured bone formation was 34%, 25%, and 35% for cell-loaded, cell-free, and untreated sockets, respectively (P < .05). At 21 days, bone formation was evident in all sites. Wound dehiscence was a complication associated with cell exclusionary membranes and resulted in local inflammation. The extraction model indicates the safety of MSCs implanted adherent to HA/TCP. Local bone repair occurred in the absence of nonspecific differentiation or migration with distant osteogenesis. An alveolar socket model may be an appropriate model for initial clinical investigation of MSC-mediated bone repair.


Secretory pattern of metabolic hormones in the lactating sow.
Two experiments were conducted to monitor hormonal changes during lactation in crossbred sows (Pietrain x German Landrace). Sows were fed twice daily without weighing the remaining food. Number of piglets was not standardized. Plasma concentrations of growth hormone (GH), prolactin (PRL), insulin-like growth factor-1 (IGF-1), IGF-2, insulin (INS), triiodothyronine (T3), thyroxin (T4), free thyroxin (FT4), non esterified fatty acids (NEFA) and glucose (GLUC) were determined by RIA, EIA or enzymatically. In exp. A (n = 5 sows), blood samples were taken via permanent jugular cannula in weekly 24 h windows at 20 min intervals and additionally once daily for 6 weeks during lactation and for 3 days after weaning. In exp. B (n = 24 sows), blood was collected by needle puncture of the ear vein 2 and 1 week before parturition, the 1st and 3rd-4th week of lactation and 1 and 2 weeks after weaning. GH (0.8 ng/ml) and PRL (10.2 ng/ml) increased with onset of lactation (3.3 resp. 91.5 ng/ml), remained at high levels (2.5-2.8 resp. 39-41 ng/ml) during the 2nd and 3rd week, declined slowly thereafter and considerably after weaning to concentrations of 0.7 resp. 2.7 ng/ml. During lactation in 4 of 5 sows in exp. A, the typical episodic secretory pattern of GH and PRL was lost due to frequent suckling. Basal values, as known from non lactating sows, were not reached and number of pulses was elevated during lactation for both pituitary hormones. Insulin levels showed a high individual variation.(ABSTRACT TRUNCATED AT 250 WORDS)


The Role of Apelin-APJ System in Diabetes and Obesity.
Nowadays, diabetes and obesity are two main health-threatening metabolic disorders in the world, which increase the risk for many chronic diseases. Apelin, a peptide hormone, exerts its effect by binding with angiotensin II protein J receptor (APJ) and is considered to be linked with diabetes and obesity. Apelin and its receptor are widely present in the body and are involved in many physiological processes, such as glucose and lipid metabolism, homeostasis, endocrine response to stress, and angiogenesis. In this review, we summarize the literatures on the role of the Apelin-APJ system in diabetes and obesity for a better understanding of the mechanism and function of apelin and its receptor in the pathophysiology of diseases that may contribute to the development of new therapies.


Hispanic/Latinx ethnic differences in the relationships between behavioral inhibition, anxiety, and substance use in youth from the ABCD cohort.
Elevated levels of behavioral inhibition (BI) may connote risk for both anxiety and substance use disorders. BI has consistently been shown to be associated with increased levels of anxiety, while the association between BI and substance use has been mixed. It is possible that the relationship between BI and substance use varies by individual difference factors. Hispanic/Latinx (H/L) youth in particular may have stronger relationships between BI, anxiety, and substance use. The present study therefore evaluated (1) the prospective relationships between BI [assessed via self-reported behavioral inhibition system (BIS) scale scores], anxiety, and substance use in youth (n = 11,876) across baseline, 1-, and 2-year follow-ups of the Adolescent Brain Cognitive Development (ABCD) Study (ages 9-12) and (2) whether these relationships differed by H/L ethnicity while covarying for average behavioral approach system scores, race, sex, age, highest parental income, highest parental education, and past-year substance use (for analyses involving substance use outcomes). Baseline levels of BIS scores predicted increased anxiety symptoms at both 1- and 2-year follow-ups and did not differ by H/L ethnicity. Baseline levels of BIS scores also prospectively predicted increased likelihood of substance use at 2-year follow-up, but only for H/L youth and not at 1-year follow-up. High scores on the BIS scale contribute risk to anxiety across ethnicities and may uniquely contribute to risk for substance use in H/L youth.


Differential expression of the two kdp operons in the nitrogen-fixing cyanobacterium Anabaena sp. strain L-31.
In several types of bacteria, the Kdp ATPase (comprising of the KdpABC complex) is an inducible, high-affinity potassium transporter that scavenges K+ from the environment. The cyanobacterium Anabaena sp. strain L-31 showed the presence of not one but two distinct kdp operons in its genome. The kdp1 consisted of kdpA1B1G1C1D genes, whereas the kdp2 contained the kdpA2B2G2C2 genes. Among the regulatory genes, the kdpD open reading frame of Anabaena sp. strain L-31 was truncated compared to the kdpD of other bacteria, whereas a kdpE-like gene was absent in the vicinity of the two kdp operons. In response to K+ limitation (<0.05 mM external K+), only kdp2 (and not kdp1) expression could be detected as a 5.3-kb transcript on Northern blots, indicating that kdpA2B2G2C2 genes constitute a polycystronic operon. Unlike E. coli, addition of osmolytes like NaCl, or a change in pH of the medium did not enhance the kdp expression in Anabaena sp. strain L-31. Interestingly, the Anabaena sp. strain L-31 kdp2 operon was strongly induced in response to desiccation stress. The addition of K+ to K+ -starved cultures resulted in repression and degradation of kdp2 transcripts. Our results clearly show that kdp2 is the major kdp operon expressed in Anabaena sp. strain L-31 and may play an important role in adaptation to K+ limitation and desiccation stress.


Etiology-based diagnostic approach to proliferative glomerulonephritis.
Proliferative glomerulonephritis (GN) often is classified based on the pattern of injury. The pattern of injury does not reveal the underlying cause. New insights into the causes of proliferative GN suggest that determining the type of deposits is more likely to provide clues to the underlying cause than determining the pattern of injury. This article proposes a new classification of proliferative GN that links findings from both immunofluorescence and light microscopy. The basis of the classification is whether the proliferative GN is immune complex mediated, pauci-immune, or complement mediated; the type of immunoglobulin deposits and complement factors then determine or suggest the underlying cause. One of the aims of the proposed classification system is to focus on the pathophysiology of the GN with emphasis on the underlying cause, leading to appropriate evaluation and management. The second aim is to simplify and standardize the classification of proliferative GN.


A gut feeling on endotoxemia: causes and consequences in chronic kidney disease.
Chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular calcification, accelerated atherosclerosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. As a consequence, inflammation is a predictor of mortality in this group of patients. Specific causes of the activation of the immune system in CKD are largely unknown. Endotoxin (ET) release to the circulation represents a potentially important target for interventions aiming to reduce mortality in CKD patients. In this minireview, we propose that there are several potential sources of endotoxemia in CKD and that gut translocation, leading to the generation of ligands of the innate immune response, represents a potentially reversible cause. Prevention of endotoxemia, through treating foci of ET (periodontal disease, catheters, vascular access) or reducing translocation from the gut, will potentially reduce the inflammatory response.


Research progress on skin photoaging and oxidative stress.
Skin photoaging, which is a kind of exogenous aging, refers to skin elasticity degradation, skin roughening, and wrinkle formation processes because of cascading reactions of a series of kinases after growth factor receptors and cytokine receptors are activated on a cell surface under the UV effect. An extensively recognized skin photoaging mechanism is free radical-oxidative stress concept, proposed by Sohal who represents the authority of the US aging studies. Over the past decade, many new developments in the oxidative stress mechanism have been achieved in terms of the occurrence, development, prevention, and treatment of photodamage.


Systemic Sarcoidosis Mimicking a Behavioural Variant of Frontotemporal Dementia.
Among rare neurological manifestations, a progressive dementia may exceptionally be the revealing clinical feature of a sarcoidosis. Diagnosis may then be difficult, especially when systemic signs are missing or latent, with a risk of therapeutic delay. We report the first case of sarcoidosis mimicking a frontotemporal dementia. A 53-year-old man presented with a dementia clinically suggestive of frontotemporal dementia, progressing slowly for about 2 years. However, MRI revealed unusual aspects, mainly large areas of T2/FLAIR hypersignal within temporal regions and cerebellum, with nodular leptomeningeal and juxtacortical Gadolinium enhancement. The patient was finally diagnosed with a systemic sarcoidosis. We discuss the differential diagnosis based on MRI aspects and review the literature on the clinical, biological, and imaging features of sarcoidosis presenting with dementia. This case demonstrates that brain imaging remains mandatory in the exploration process of a patient with dementia. Although the patient presented with rather typical features of a behavioural variant of frontotemporal dementia, the MRI aspect was the key exploration that leaded to the diagnosis.


Racial disparities in health insurance, triple-negative breast cancer diagnosis, tumor stage, treatment and survival in a large nationwide SEER cohort in the United States.
It remains unclear whether there are racial disparities in mortality between women of different races who have the same subtype of breast cancer when tumor stage and size and treatment are controlled for. The present study aimed to investigate whether racial disparities in mortality existed between women of different races who had the same subtype of breast cancer when health insurance, tumor stage and size and treatment were controlled for in a large cohort of women with breast cancer in the United States. This study identified 399,564 women who were diagnosed with incident breast cancer at age ≥20 years between 2010 and 2016 in 17 Surveillance, Epidemiology and End Results (SEER) registries, including 277,319 non-Hispanic white (white), 44,149 non-Hispanic black (black), 34,141 non-Hispanic Asian or Pacific Islander (Asian) and 43,955 Hispanic women. White and Asian women exhibited a lower proportion of triple-negative breast cancer (9.8 and 9.1% respectively) than black (20.8%) and Hispanic women (12.6%). Black women had a significantly higher risk of all-cause mortality compared with white women in only those with triple-negative breast cancer (hazard ratio: 1.39, 95% CI: 1.29-1.51) and those with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive breast cancer (1.53, 1.48-1.58) after adjusting for confounders. In those with hormone receptor-positive breast cancer, regardless of HER2 receptor status, the risk of all-cause mortality was not statistically different between black and white women, while the risk of breast cancer-specific mortality was significantly higher in all subtypes of breast cancer among black women. There were racial disparities in the presentation of triple-negative breast cancer and in all-cause and breast cancer specific mortality following stratification by triple-negative status and adjusting for tumor stage, size, grade and treatment.


[Serious complications to a weight loss programme with HCG].
A 28-year-old woman presented with abdominal pain. Prior to admission she had injected human chorionic gonadotropin (hCG) intramuscularly as part of a weight loss programme. A computed tomography detected a thrombosis of the superior mesenteric vein and with a gynaecologic scan she was found to be six weeks pregnant despite using oral contraception. Treatment with anticoagulant therapy was started, and a surgical abortion was performed. hCG bought illegal is used as a part of a weight loss program. Whether HCG injected in small amounts is a risk factor of venous thrombosis and whether it is able to reduce the effect of oral contraception is unknown.


Arterial pseudoaneurysms complicating pancreatitis: literature review.
Arterial pseudoaneurysm formation of visceral arteries as a vascular complication of pancreatitis, either acute or chronic, is an uncommon phenomenon. This review article discusses the incidence, pathophysiology, imaging, treatment strategies, and prognosis of mesenteric pseudoaneurysms complicating pancreatitis.


Allergic diagnosis: skin testing and rast.
In a minority of patients with allergic rhinitis, diagnosis of the offending allergens is necessary for control of symptoms. Skin endpoint titration (SET) testing, the most advanced form of skin testing, and the radioallergosorbent test (RAST) are the only two diagnostic tests that give quantitative results upon which to base immunotherapy. Patients who undergo diagnostic testing must understand the commitment involved in a program of immunotherapy. This review hopes to enable clinicians to better understand the techniques of skin testing and RAST and how and when these tests may be of use to their patients suffering from allergic rhinitis.


Genotyping of the prion protein gene at codon 129.
Sporadic, iatrogenic and new variant forms of Creutzfeldt-Jakob disease are associated with a predisposition for disease depending on a homozygosity at amino acid residue 129 of the prion protein gene (PRNP). A novel polymerase chain reaction/restriction digestion assay to screen for this polymorphism was developed and proved after comparison with a previously used method to be advantageous. Furthermore, for prevention of incorrect results an internal control for the restriction digestion was constructed. The feasibility of this method was tested in a cohort of 300 healthy Caucasian subjects. Of this normal population, 48.7% were heterozygous at codon 129, 43% homozygous for methionine and 8.3% for valine.


Modern trends in the development of bacterial vaccines for human use.
The development of vaccines against infectious diseases is one of the great medical achievements of the 20th century. What other medical measure had such an influence on the statistical prolongation of life, as the use of vaccines did? The successful development of today's vaccines was from the beginning due to the intensive cooperation between the basic research sciences (e.g. bacteriology virology, chemistry, immunology) and the applied sciences (e.g. medicine-practiced). During the last few years newly developed techniques have awakened hopes for the development of new vaccines which are better tolerable and more effective. Molecular biologic methods have shown first successes in the development of epitope vaccines. Monoclonal anti-idiotype antibodies are being used in active protection experiments. Modern galenic preparations can perhaps one day replace the parenteral administration of antigens. In the following some of the new techniques are listed and their significance for the development of new vaccines discussed.


Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes that requires multitargeted treatment. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) improve cholinergic signaling in the central nervous system and thus AChE inhibitors are well established in the therapy of AD to improve memory disturbances and other cognitive symptoms. On the other hand, AD patients benefit from reduction of pathologic glutamate-induced, Ca(2+)-mediated excitotoxicity by the N-methyl-d-aspartate receptor (NR) antagonist memantine. New drugs that simultaneously affect both cholinergic transmission and glutamate-induced excitotoxicity may further improve AD treatment. While connecting beta-carboline units by alkylene spacers in two different series of compounds and subsequent evaluation of their AChE/BChE-inhibitory potential, we found that several of these bivalent beta-carbolines were potent NR blockers. The most promising compound was a N(9)-homobivalent beta-carboline with a nonylene spacer, which displayed IC(50) values of 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 microM for NR, respectively.


Surface-enhanced Raman scattering on colloidal nanostructures.
Surface-enhanced Raman scattering combines extremely high sensitivity, due to enhanced Raman cross-sections comparable or even better than fluorescence, with the observation of vibrational spectra of adsorbed species, providing one of the most incisive analytical methods for chemical and biochemical detection and analysis. SERS spectra are observed from a molecule-nanostructure enhancing system. This symbiosis molecule-nanostructure is a fertile ground for theoretical developments and a realm of applications from single molecule detection to biomedical diagnostic and techniques for nanostructure characterization.


Eagle's Syndrome Presenting as Peripheral Facial Palsy.
Eagle's syndrome (ES) is the elongation of the ossified styloid process that causes symptoms such as foreign body sensation, neck pain, and odynophagia. A styloid process greater than 25 mm in length should be considered abnormal. Facial palsy is a condition that affects the facial nerve and results in weakness or total paralysis of the facial muscles that control expression. Here, we describe a rare presentation of ES presenting as facial palsy. We present the case of a 62-year-old female who was admitted to the emergency department with right peripheral facial palsy. A computed tomography (CT) scan of the neck confirmed the diagnosis. The patient underwent conservative management and physical therapy, which resulted in good evolution with an improvement of symptoms. She was referred to the otorhinolaryngologist for surgical evaluation.


Umbilical cord blood stem cells: application for the treatment of patients with hemoglobinopathies.
Even though there is recognized morbidity and death associated with bone marrow transplantation, this procedure has been performed successfully in a substantial number of patients with hemoglobinopathies. However, finding a suitable related donor is often difficult and the morbidity associated with the use of unrelated donors is high. Several reports indicate that fewer than 30% of patients with thalassemia major and fewer than 20% of patients with sickle cell anemia have histocompatible siblings. Human umbilical cord blood (UCB) contains hematopoietic stem cells capable of reconstituting bone marrow. To date, approximately 200 transplantations have been performed with UCBs. Early results suggest that, even with substantial human leukocyte antigen (HLA) incompatibility, a decrease in the incidence of graft-versus-host disease occurs with cord blood. The extent to which HLA incompatibility can be tolerated when cord blood is used has not been determined. These results raise the possibility that UCB obtained from unrelated donors could be used for transplantation in patients with hemoglobinopathies. This review summarizes current data on UCB stem cells used for transplantation in hematologic diseases. The review contains a discussion of the potential uses of UCB for patients with hemoglobinopathies and the value of programs designed to collect UCB from newborn infants with hemoglobinopathies, from siblings of patients with hemoglobinopathies, and from groups of ethnic minorities similar to those in which hemoglobinopathies are found.


Avoiding Above-the-Knee Amputation with a Free Tibiofibular-Talocalcaneal Fillet Flap and Free Latissimus Dorsi Flap.
Despite the advances achieved in reconstructive surgery, amputation is still the only option after some severe traumas. Preservation of the knee joint is considered a significant functional advantage. We present the case of a 39-year-old man with a comminuted Gustilo type IIIC open tibia fracture with massive bone loss. To achieve a well-fashioned amputation stump and preserve the knee joint, a free osteocutaneous fillet flap was performed, including the distal tibia and fibula, talus, and calcaneus bones. As a result, a sensate and long amputation stump covered with thick skin from the sole of the foot provided a stable coverage with an excellent functional result and adjustment to prosthesis.


Chinese expert consensus on the multidisciplinary management of pneumonitis associated with immune checkpoint inhibitor.
Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in-depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.


[Acute hepatocellular lesion induced by amoxicillin-clavulanic acid].
Since first description in 1988, numerous cases of amoxycillin-clavulanic acid hepatotoxicity have been reported. Most of them are cholestatic hepatitis. A case of acute hepatocellular injury by amoxycillin-clavulanic acid is reported in a 23-years-old male, with a favourable outcome after 18 weeks.


The signal pathways and treatment of cytokine storm in COVID-19.
The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.


Lactic acid bacteria differentially regulate filamentation in two heritable cell types of the human fungal pathogen Candida albicans.
Microorganisms rarely exist as single species in natural environments. The opportunistic fungal pathogen Candida albicans and lactic acid bacteria (LAB) are common members of the microbiota of several human niches such as the mouth, gut and vagina. Lactic acid bacteria are known to suppress filamentation, a key virulence feature of C. albicans, through the production of lactic acid and other metabolites. Here we report that C. albicans cells switch between two heritable cell types, white and opaque, to undergo filamentation to adapt to diversified environments. We show that acidic pH conditions caused by LAB and low temperatures support opaque cell filamentation, while neutral pH conditions and high temperatures promote white cell filamentation. The cAMP signalling pathway and the Rfg1 transcription factor play major roles in regulating the responses to these conditions. This cell type-specific response of C. albicans to different environmental conditions reflects its elaborate regulatory control of phenotypic plasticity.


Diagnosis and serial sonography of a proximal fifth metatarsal stress fracture.
The purpose of this report is to describe a fifth metatarsal stress fracture that was not detectable using conventional radiographs and was identified with diagnostic ultrasonography (US), confirmed with computed tomography, and followed through symptom resolution with US. A 68-year-old woman presented to a chiropractic teaching clinic for evaluation of right foot pain. Diagnostic US examination using an 8- to 15-MHz linear array transducer showed increased vascularity, periosteal elevation, and cortical disruption of the proximal diaphysis of the fifth metatarsal suggestive of a stress fracture. The patient was referred to an orthopedic specialist for comanagement. The patient was treated by an orthopedist who confirmed a stress fracture using computed tomography, and she was fit with a short-leg walking boot. Serial US images were obtained to document fracture healing and exclude complications. After 6 months, the patient was asymptomatic and had resumed all of her daily activities. We report a case of a proximal fifth metatarsal stress fracture that was visualized with US and followed through symptom resolution by serial examinations.


Vaccination Against SARS-CoV-2 Protects from COVID-19-induced Endothelial Dysfunction.
Coronavirus Disease-19 (COVID-19) is implicated in endotheliitis, which adversely affects cardiovascular events. The impact of vaccination with COVID-19 on the clinical outcome of patients is documented. To evaluate the impact of vaccination with COVID-19 on the severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) infection-related endothelial impairment. We enrolled 45 patients hospitalized for COVID-19 (either vaccinated or not against SARS-CoV-2). Clinical and laboratory data were collected, and brachial artery flow-mediated dilation (FMD) was evaluated. Subjects without COVID-19 were used as the control group. There was no difference in age (64.7 ± 7.5 years vs. 61.2 ± 11.1 years vs. 62.4 ± 9.5, p = 0.28), male sex (49% vs. 60% vs. 52%, p = 0.71), control subjects, vaccinated, and unvaccinated subjects with COVID-19, respectively. Of the patients with COVID-19, 44% were vaccinated against SARS-CoV-2. Unvaccinated COVID-19 patients had significantly impaired FMD compared to vaccinated COVID-19 patients and Control subjects (2.05 ± 2.41 % vs. 7.24 ± 2.52% vs. 7.36 ± 2.94 %, p <0.001). Importantly, post hoc tests revealed that unvaccinated COVID-19 patients had significantly impaired FMD from both Vaccinated COVID-19 subjects (p <0.001) and from Control subjects (p <0.001). There was no difference in FMD between the control group and the vaccinated COVID-19 group (p = 0.99). Hospitalized patients with COVID-19 present endothelial dysfunction in the acute phase of the disease. Endothelial function in unvaccinated patients with COVID-19 is impaired compared to control subjects as well compared to vaccinated patients with COVID-19. Vaccinated hospitalized subjects with COVID-19 do not show endothelial dysfunction, strengthening the protective role of vaccination against SARS-CoV-2.


Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype.
Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis. We hypothesized that abnormalities in expression of these proteins may explain the radiosensitivity of some of our cancer patients. The cells from one patient showed a reproducibly consistent expression reduction in two complex-forming DNA double-strand break repair protein components (DNA Ligase IV and XRCC4). We also showed a corresponding reduction in both gene products at the mRNA level. Additionally, the mRNA inducibility by ionizing radiation was increased for one of the proteins in the patient's cells. We confirmed the likely functional significance of the non-homologous end-joining (NHEJ) expression abnormalities with a DNA double strand break (DNA DSB) repair assay. We have identified a novel biological phenotype linked to clinical radiosensitivity. This is important in that very few molecular defects are known in human radiotherapy subjects. Such knowledge may contribute to the understanding of radiation response mechanisms in cancer patients and to personalization of radiotherapy.


Membrane-bound heparin-binding epidermal growth factor like growth factor regulates E-cadherin expression in pancreatic carcinoma cells.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF growth factor family. Initially synthesized as a membrane-bound precursor (pro-HB-EGF), it is cleaved at the juxtamembrane domain to release the soluble form of HB-EGF (s-HB-EGF) by sheddases, including matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases. This is a process referred to as ectodomain shedding and is implicated in the process of all ligands of the EGF receptor (EGFR) family. The tumorigenic potential of s-HB-EGF has been studied extensively; however, the role of pro-HB-EGF in tumor progression is unknown, despite the fact that a considerable amount of pro-HB-EGF remains on the cell membrane. Our data here clearly indicated the distinct role of pro-HB-EGF in the regulation of E-cadherin expression and the epithelial-mesenchymal transition. We showed here that the expression of pro-HB-EGF was associated with the differentiation status in pancreatic tumors and cell lines. Expression of noncleaved pro-HB-EGF in pancreatic cells resulted in the up-regulation of E-cadherin through suppression of ZEB1, which is a transcriptional repressor of E-cadherin. Inhibition of HB-EGF shedding using a MMP inhibitor, GM6001, also dramatically augmented the E-cadherin expression while suppressing the EGFR activation. Moreover, up-regulation of E-cadherin by pro-HB-EGF not only resulted in cellular morphologic change but also decreased cell motility and enhanced apoptotic sensitivity in response to gemcitabine-erlotinib treatment. Collectively, our data defined a distinct role of pro-HB-EGF in the regulation of E-cadherin, suggesting that inhibition of shedding may be a novel approach to suppress pancreatic metastasis and sensitize cells to cancer therapy.


Therapeutic Interventions for the Suppression of Alzheimer's Disease: Quest for a Remedy.
Protein aggregation is facilitated by the generation of partially folded intermediates that lack most of the tertiary interactions, but retain the complete secondary structure. These partially folded states cross-link each other to form protein aggregates. Protein aggregates in an advanced stage result in the formation of amyloid fibrils, which have high tensile strength. These amyloid fibrils are associated with a number of pathologies, especially Alzheimer's disease, which involves the aggregation of the Aβ peptide. In recent years, much attention has been paid to the generation of potent therapeutics to reduce Aβ peptide fibrillation. This review summarizes the range of molecules used for this therapy, showing their potency against Aβ amyloids, and suggests a positive future for the eradication of this dreaded disease.


Major salivary gland enlargement in IgG4-related disease is associated with multiorgan involvement and higher basal disease activity.
Objective: To evaluate if major salivary gland enlargement in patients with IgG4-related disease (IgG4-RD) is associated with systemic involvement.Methods: We included 47 patients with diagnosis of IgG4-RD. We retrospectively collected demographics, organ involvement, disease activity and damage assessed by the IgG4-RD Responder Index (IgG4-RD RI) and treatment.Results: 25 patients (53%) were men, mean age 50.8 years and median disease duration 27 months. Most frequently anatomic sites affected were lymph nodes 55%, pancreas 51% and lacrimal glands 43%. We observed major salivary gland involvement in 22 (46.8%) patients. When we compared patients with (n = 22) vs. without (n = 25) salivary gland enlargement, the first group had a higher number of affected organs, a higher prevalence of lacrimal glands, lymph nodes, and lung involvement, rheumatoid factor positivity, azathioprine and prednisone use, as well as a higher baseline IgG4-RD RI and a longer delay in diagnosis. At logistic regression analysis we found an association of major salivary gland enlargement with the basal IgG4-RD RI (OR 1.37, 95%CI 1.09-1.61, p = .001) and with lacrimal gland involvement (OR 34.7, 95%CI 4.6-258, p = .001).Conclusion: Our study highlights the systemic nature of IgG4-RD. Patients with major salivary gland enlargement should be routinely screened for multi-organ disease.


Cigarette smoking among Jordanian adults.
The objectives were to determine the rate of cigarette smoking and correlates of its use among a sample of Jordanian adults (N = 600). A survey-based, cross-sectional study was conducted with a convenient sample. Logistic regression was used to determine predictors of being a cigarette smoker. Approximately half of the population (45%) had smoked a cigarette in the past month, 40% in the past week, and 36% in past 24 hours. These findings underscore the magnitude of the smoking problem in the Jordanian population and the urgent need for effective interventions. Future research should focus on developing interventions that incorporate the predictors identified.


[Functional anatomy of the elbow joint].
An attempt has been made to describe the combined action of the bony elements of the elbow joint, together with the capsular ligaments, as a single unit. Particular emphasis is laid upon the mechanisms that prevent abrupt limitation of movement. The account of the periarticular structures, including the adjacent muscles, is followed by a discussion of the various possible surgical approaches to the joint. Finally, a general survey is given of the kinematics and kinetics of the elbow joint. It is suggested that the distribution of the hyaline articular cartilage and the density of the underlying bone are morphological reflections of the stresses acting upon the joint. It follows that the axial pressure acts upon both the ulnar and the radial components of the elbow; therefore, if the joint is to remain stable, at least one of its distal bony elements must be functionally effective.


Isometric skeletal muscle contractile properties in common strains of male laboratory mice.
Assessing contractile function of skeletal muscle in murine models is a commonly employed laboratory technique that investigators utilize to measure the impact of genetic manipulations, drug efficacy, or other therapeutic interventions. Often overlooked is the potential for the strain of the mouse to influence the functional properties of the skeletal muscle. Thus, we sought to characterize commonly assessed isometric force measures in the hindlimb muscles across a variety of mouse strains. Using 6-8-week-old male mice, we measured isometric force, fatigue susceptibility, relaxation kinetics, muscle mass, myofiber cross-sectional area, and fiber type composition of the extensor digitorum longus (EDL) and soleus muscles in C57BL/6NJ, BALB/cJ, FVB/NJ, C57BL/6J, and C57BL/10 mice. The data demonstrate both unique differences and a number of similarities between both muscles in the various genetic backgrounds of mice. Soleus muscle specific force (i.e., force per unit size) exhibited higher variation across strains while specific force of the EDL muscle exhibited minimal variation. In contrast, absolute force differed only in a few mouse strains whereas analysis of muscle morphology revealed many distinctions when compared across all the groups. Collectively, the data suggest that the strain of the mouse can potentially influence the measured biological outcome and may possibly promote a synergistic effect with any genetic manipulation or therapeutic intervention. Thus, it is critical for the investigator to carefully consider the genetic background of the mouse used in the experimental design and precisely document the strain of mouse employed during publication.


Acute adenoviral infection of a graft by serotype 35 following renal transplantation.
Adenoviral infections of immunocompetent patients usually present as self-limiting pharyngitis, gastroenteritis, urocystitis, or conjunctivitis. In immunosuppressed patients, development of the illness can be severe, even life-threatening or fatal, and therapeutical intervention is difficult. Previous case reports of adenoviral infections after kidney transplantation have described a symptomatology of hemorrhagic cystitis, fever, renal dysfunction, and rarely fatal systemic dissemination. Here we report on a 46-year-old female renal transplant recipient suffering from adenoviral serotype 35 nephritis of the donor organ 29 days after transplantation. In this case, the main symptoms of the adenoviral infection were high fever and progressive renal failure of the transplanted organ. At the peak of the clinical symptoms, owing to histological and immunohistochemical evaluations of a kidney biopsy, we were able to establish the diagnosis in time so that adequate therapy could be employed. Immunosuppression was reduced and modified, and a self-limiting course of the infection was observed, followed by significant improvement of graft function. Subsequent to histological diagnosis, adenoviral particles were isolated from urine and identified as adenovirus serotype 35. Adenoviral nephritis of the transplanted organ should be considered in the differential diagnosis of persistent anuria after kidney transplantation. Our case highlights the importance of applying all possible diagnostic techniques, including histological evaluation of renal biopsies.


Prevalence of undiagnosed HIV infection in patients with ocular surface squamous neoplasia in a tertiary center in Karnataka, South India.
To evaluate the prevalence of undiagnosed and asymptomatic human immunodeficiency virus (HIV) infection in patients with ocular surface squamous neoplasia (OSSN) in a referral hospital in Karnataka, South India. A consecutive series of patients presenting with OSSN were evaluated in an academic center during January 2009 to June 2010. A detailed history was obtained and physical examination in 25 consecutive patients with OSSN was performed. Twenty-three patients (88%) agreed to undergo serological HIV testing. Of these, 2 were excluded from the current study because they had xeroderma pigmentosa, a known predisposing factor for OSSN. Of the 21 patients, 6 (29%) patients were HIV positive. None of the patients had previous HIV testing. The median age of presentation among HIV-positive patients was 36 years, whereas it was 54 years among HIV-negative patients. The mean CD4 count in HIV-positive patients was 133 cells per mm, and all patients were started on antiretroviral treatment. The conjunctival tumor may be the primary and the only apparent manifestation of HIV in patients presenting with OSSN, and the ophthalmologist needs to be aware of this association.


Potential role of NF-kB and RXR beta like proteins in interferon induced HLA class I and beta globin gene transcription in K562 erythroleukaemia cells.
Positive effects of biological response modifiers on cancer cells are usually measured using markers for increased immunogenicity as well as those for increased differentiation of the cells. An increase in levels of HLA class I antigens and the adult (beta) globin molecules are two such markers that may be used to assess the effect of modulators like interferons on the K562 erythroleukaemia cell line. Although interferon mediated up regulation of gene expression is thought to be primarily regulated by binding of proteins to the Interferon responsive cis elements in the promoters of IFN responsive genes, recent evidence has shown the induction of other transcriptional activators in response to IFN treatment. We present evidence for one such instance wherein up regulation of HLA class I and beta globin gene transcription are accompanied by induction of binding activities similar to RXR beta and kB proteins in K562 cells.


The protective role of fruits and vegetables against radiation-induced cancer.
The role of fruits and vegetables in protecting against radiation-induced cancer and the positive evidence from epidemiology and ancillary investigations are discussed in this review. The recently reported Hiroshima and Nagasaki atomic bomb survivor studies provide strong evidence for the protective role of fruits and vegetables against radiation-induced cancer. The anticarcinogenic substances contained in, and the anticarcinogenic mechanisms proposed for, fruits and vegetables are reviewed. The anticarcinogenic effectiveness of fruits and vegetables are compared with that of dietary supplements. The reasons for the observed superiority of fruits and vegetables are advanced.


Report of proceedings of the national meeting on "Guidelines for Immunophenotyping of Hematolymphoid Neoplasms by Flow Cytometry".
Immunophenotyping of hematolymphoid neoplasms is being done in many laboratories in India. The first national meeting on "Guidelines for Immunophenotyping of Hematolymphoid Neoplasms by Flow Cytometry" was held on 14 March 2008 in Mumbai, India. To achieve uniformity in the laboratory practice regarding antibody panel selection in diagnosing hematolymphoid neoplasms. Members of the Inter-Laboratory Comparison Program (ILCP) group in Mumbai prepared a draft regarding immunophenotypic panel selection for acute leukemias (ALs) and chronic lymphoproliferative disorders (CLPDs), which was further circulated among national and international cytometrists, hematopathologists, and oncologists for their written inputs, suggestions, proposed modifications; as well as their indications, if any, of the recommendations not being acceptable. Practice-based questionnaire was circulated among all the participants. Consensus was attained, and the panel recommended the use of a minimal screening panel, followed by a secondary directed panel. The aim of the minimal screening panel would be to provide a diagnosis of all commonly occurring hematolymphoid neoplasms without the need of additional antibodies in most cases. Thus we could attain a consensus for our guidelines in selecting panels for ALs and CLPDs. The guideline is an attempt to formulate a minimal panel for immunophenotyping of hematolymphoid neoplasms. Laboratories are encouraged to add additional antibodies to the above panel to increase the sensitivity; however, they should refrain from immunophenotyping with fewer antibodies. This national guideline hopefully brings about uniformity and comparability in reporting of leukemia and lymphoma and bridges the divide between low-cost reporting and an accurate diagnosis.


Effectiveness of antidepressants and predictors of treatment response for depressed HIV patients in Uganda.
Antidepressant medication is well established for the treatment of depression but little is known about its effectiveness for HIV populations in sub-Saharan Africa. This study examined the effectiveness of antidepressant treatment and predictors of treatment response among depressed HIV patients in Uganda. Data were obtained from two open-label trials in which 184 HIV patients were diagnosed with depression and started on antidepressants. Data at treatment baseline and month 6 were compared to assess treatment response, and baseline predictors of response were assessed. A total of 154 completed month 6, of whom 122 (79%) had responded to treatment and were no longer depressed (Patient Health Questionnaire-9, score < 5). Bivariate analysis found that education, CD4 count, general health functioning, physical health, pain, quality of life and social support variables were associated with antidepressant treatment response; however, only secondary education and social support independently predicted treatment response in logistic multiple regression analysis. Baseline depression severity was not associated with treatment response. In conclusion, antidepressants are effective in treating both moderate and more severe depression among persons living with HIV in Uganda, and education [OR (95% CI) = 4.33 (1.33-14.11)] and social support [OR (95% CI) = 1.54 (1.03-2.30)] were most predictive of treatment response.


Critical determinants of metastasis.
The major cause of death from cancer is due to metastases that are resistant to conventional therapies. Several reasons account for the failure to treat metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects for a small subpopulation of cells that preexist within a parental neoplasm. Third, and perhaps the greatest obstacle for therapy, is that the outcome of metastasis depends on multiple interactions ('cross-talk') of metastatic cells with homeostatic mechanisms which the tumor cells usurp. Most recent data demonstrate that the organ microenvironment can influence the growth, invasion, and response of metastases to chemotherapy. Therapy of metastasis should therefore be targeted against both the metastatic tumor cells and the homeostatic factors that promote metastasis.


Chemical Composition and Biological Activity of Essential Oils from Different Species of Piper from Panama.
The chemical composition of leaf essential oils from 11 species of Piper from Panama was analyzed by a combination GC-FID and GC-MS procedures. Six of them had sesquiterpene hydrocarbons as major constituents, three were characterized by monoterpene hydrocarbons, one by a diterpene, and one by a phenylpropanoid, dillapiole. The main components identified in each species were: cembratrienol (25.4 %) in Piper augustum; β-pinene (26.6 %) in Piper corrugatum; α-pinene (19.4 %) in Piper curtispicum; trans-β-farnesene (63.7 %) in Piper darienense; p-cymene (43.9 %) in Piper grande; dillapiole (57.7 %) in Piper hispidum; linalool (14.5 %), α-phellandrene (13.8 %), and limonene (12.2 %) in Piper jacquemontianum; β-caryophyllene (45.2 %) in Piper longispicum; linalool (16.5 %), α-phellandrene (11.8 %), limonene (11.4 %), and p-cymene (9.0 %) in Piper multiplinervium; β-selinene (19.0 %), β-elemene (16.1 %), and α-selinene (15.5 %) in Piper reticulatum; and germacrene D (19.7 %) in Piper trigonum. The essential oils of P. hispidum and P. longispicum at a concentration of 250 µg/mL showed larvicidal activity against Aedes aegypti, while the oils from P. curtispicum, P. multiplinervium, P. reticulatum, and P. trigonum were inactive (LC100 ≥ 500 µg/mL). The essential oils of P. grande, P. jacquemontianum, and P. multiplinervium showed no significant antifungal activity (MIC > 250 µg/mL) against several yeasts and filamentous fungal strains.


Multi-channel MRI segmentation of eye structures and tumors using patient-specific features.
Retinoblastoma and uveal melanoma are fast spreading eye tumors usually diagnosed by using 2D Fundus Image Photography (Fundus) and 2D Ultrasound (US). Diagnosis and treatment planning of such diseases often require additional complementary imaging to confirm the tumor extend via 3D Magnetic Resonance Imaging (MRI). In this context, having automatic segmentations to estimate the size and the distribution of the pathological tissue would be advantageous towards tumor characterization. Until now, the alternative has been the manual delineation of eye structures, a rather time consuming and error-prone task, to be conducted in multiple MRI sequences simultaneously. This situation, and the lack of tools for accurate eye MRI analysis, reduces the interest in MRI beyond the qualitative evaluation of the optic nerve invasion and the confirmation of recurrent malignancies below calcified tumors. In this manuscript, we propose a new framework for the automatic segmentation of eye structures and ocular tumors in multi-sequence MRI. Our key contribution is the introduction of a pathological eye model from which Eye Patient-Specific Features (EPSF) can be computed. These features combine intensity and shape information of pathological tissue while embedded in healthy structures of the eye. We assess our work on a dataset of pathological patient eyes by computing the Dice Similarity Coefficient (DSC) of the sclera, the cornea, the vitreous humor, the lens and the tumor. In addition, we quantitatively show the superior performance of our pathological eye model as compared to the segmentation obtained by using a healthy model (over 4% DSC) and demonstrate the relevance of our EPSF, which improve the final segmentation regardless of the classifier employed.


Complete genome sequence and comparative genomic analysis of Mycobacterium massiliense JCM 15300 in the Mycobacterium abscessus group reveal a conserved genomic island MmGI-1 related to putative lipid metabolism.
Mycobacterium abscessus group subsp., such as M. massiliense, M. abscessus sensu stricto and M. bolletii, are an environmental organism found in soil, water and other ecological niches, and have been isolated from respiratory tract infection, skin and soft tissue infection, postoperative infection of cosmetic surgery. To determine the unique genetic feature of M. massiliense, we sequenced the complete genome of M. massiliense type strain JCM 15300 (corresponding to CCUG 48898). Comparative genomic analysis was performed among Mycobacterium spp. and among M. abscessus group subspp., showing that additional ß-oxidation-related genes and, notably, the mammalian cell entry (mce) operon were located on a genomic island, M. massiliense Genomic Island 1 (MmGI-1), in M. massiliense. In addition, putative anaerobic respiration system-related genes and additional mycolic acid cyclopropane synthetase-related genes were found uniquely in M. massiliense. Japanese isolates of M. massiliense also frequently possess the MmGI-1 (14/44, approximately 32%) and three unique conserved regions (26/44; approximately 60%, 34/44; approximately 77% and 40/44; approximately 91%), as well as isolates of other countries (Malaysia, France, United Kingdom and United States). The well-conserved genomic island MmGI-1 may play an important role in high growth potential with additional lipid metabolism, extra factors for survival in the environment or synthesis of complex membrane-associated lipids. ORFs on MmGI-1 showed similarities to ORFs of phylogenetically distant M. avium complex (MAC), suggesting that horizontal gene transfer or genetic recombination events might have occurred within MmGI-1 among M. massiliense and MAC.


Pharmacologic pain. Management for cancer patients at home.
Pain management is one of the most important responsibilities of the home care nurse serving cancer patients. Patients and caregivers often fear uncontrolled pain, and need frequent reassurance that effective pain control can be achieved. This article discusses the etiology and types of cancer pain, pain assessment, pharmacologic pain management interventions, and evaluation of pain management for home care patients.


The TAK1-NF-κB axis as therapeutic target for AML.
Development and maintenance of leukemia can be partially attributed to alterations in (anti)-apoptotic gene expression. Genome-wide transcriptome analyses revealed that 89 apoptosis-associated genes were differentially expressed between patient acute myeloid leukemia (AML) CD34(+) cells and normal bone marrow (NBM) CD34(+) cells. Among these, transforming growth factor-β activated kinase 1 (TAK1) was strongly upregulated in AML CD34(+) cells. Genetic downmodulation or pharmacologic inhibition of TAK1 activity strongly impaired primary AML cell survival and cobblestone formation in stromal cocultures. TAK1 inhibition was mainly due to blockade of the nuclear factor κB (NF-κB) pathway, as TAK1 inhibition resulted in reduced levels of P-IκBα and p65 activity. Overexpression of a constitutive active variant of NF-κB partially rescued TAK1-depleted cells from apoptosis. Importantly, NBM CD34(+) cells were less sensitive to TAK1 inhibition compared with AML CD34(+) cells. Knockdown of TAK1 also severely impaired leukemia development in vivo and prolonged overall survival in a humanized xenograft mouse model. In conclusion, our results indicate that TAK1 is frequently overexpressed in AML CD34(+) cells, and that TAK1 inhibition efficiently targets leukemic stem/progenitor cells in an NF-κB-dependent manner.


Presynaptic regulation of neurotransmitter release in hypertension.
1. The present review discusses evidence in support of the concept that alterations in sympathetic neurotransmitter release might contribute to the pathogenesis of hypertension. 2. Studies suggest that changes in sympathetic nervous activity in both the central and peripheral nervous systems participate in blood pressure control. 3. In the periphery increased release of norepinephrine from vascular adrenergic neurons might lead to the enhanced vasoconstrictor responses and thus to an elevation in systemic blood pressure. 4. The amount of neurotransmitter release from sympathetic nerve endings can be regulated by autoregulatory systems by presynaptic receptors located on nerve terminals. 5. It has been proposed that alterations to sympathetic nervous activity of hypertension might be partially due to abnormalities in presynaptic modulation of neurotransmitter release in central and peripheral tissues. 6. This article summarizes the results of studies to evaluate presynaptic receptor functions and sympathetic neurotransmitter release in hypertension.


Improved Dose Conformity for Adjacent Targets: A Novel Planning Technique for Gamma Knife Stereotactic Radiosurgery.
Purpose In the current Gamma Knife (GK) planning system (GammaPlan, version 10.2, Elekta AB, Stockholm, Sweden), multiple adjacent brain metastasis (BMs) had to be planned sequentially if BMs were drawn separately, leading to less conformal target dose in the composite plan due to inter-target dose contribution and fine-tuning of the shots being quite tedious. We proposed a method to improve target dose conformality and planning efficiency for such cases. Methods and Materials Fifteen patients with multiple BMs treated on the Leksell GK Perfexion system were retrospectively replanned in the Institutional Review Board (IRB) approved study. The recruitment criterion was all the BMs should be entirely encompassed within the maximum dose grid allowed in the GammaPlan. The BMs were first planned sequentially as routine clinic cases. The contours of the BMs were then exported to the VelocityAI (Varian, CA, USA) to generate a composite contour after a union operation, and all the BMs were planned again simultaneously using this composite contour in the GammaPlan. The inverse planning (IP) was employed in both methods with the same treatment time allowed for a fair plan comparison. Dose evaluation was performed in the VelocityAI with all planning magnetic resonance (MR) images, structure set and dose were exported to the VelocityAI. The dosimetery parameters, including conformality index (CI), V20Gy, V16Gy, V12Gy, and V5Gy, were compared between the two methods. Results The planning results from both methods were reviewed qualitatively and quantitatively. The proposed method exhibited superior CI, except for an outlier case with very tiny BMs. The mean and standard deviation (std.) of the Paddick CI for all patients were 0.76±0.11 for the proposed method, comparing to 0.69±0.13 for the sequential method. The V20Gy, V16Gy, V12Gy, and V5Gy for the proposed method were 10.9±0.9%, 9.5±10.2%, 6.2±16.4% and 3.3±21.8%, all lower than those from the sequential method. Conclusions The proposed method showed improved target dose conformality for all cases except for very tiny BMs. Planning efficiency is considerably better with the combined target technique. The improved dose conformality will be beneficial to patients in long term with lowered risk of radiation necrosis after GK stereotactic radiosurgery (SRS).


Characterization of Austrian koi herpesvirus samples based on the ORF40 region.
Using a PCR that amplifies a region of the thymidine kinase (TK) gene, an epidemic spread of koi herpesvirus (KHV) was determined in koi carps in Austria in 2007. A total of 15 virus samples from different locations in Austria were analyzed to determine their genetic relatedness following PCR and nucleic acid sequencing of the open reading frame 40 (ORF40) region of the KHV genome. ORF40-specific PCR amplification products that were obtained from tissue samples shared 100% nucleotide sequence identity with the published sequence of the Japanese strain of KHV. The ORF40 sequence of one isolate from the UK that was included in the present study was 100% identical with the published sequence of an Israeli strain of KHV. This is the first study that used a larger number of samples and a PCR method, which allowed distinguishing all 3 strains of KHV. The present investigation provides information on the epidemiology of KHV infections in Europe and describes a useful molecular tool for epidemiological studies.


Frequency and locations of systemic metastases in Merkel cell carcinoma by imaging.
The primary neuroendocrine skin cancer, Merkel cell carcinoma (MCC), has a well-known predilection to metastasize systemically. However, the experience of systemic metastases in MCC is mainly disseminated through case reports due to the rarity of MCC. To elucidate the frequency and locations of systemic metastasis in MCC by reviewing the imaging of patients with metastatic MCC in a national cohort. Patients with diagnosed metastatic MCC by imaging studies in Finland during 1999-2012 were included in this study. We reviewed their imaging studies to evaluate the most frequent sites for systemic metastasis and determined the latency between the primary tumor diagnosis and systemic metastasis. The material includes 30 MCC patients with complete imaging series and 187 examinations, of which 102 (54%) were CT images. The mean latency from the primary tumor diagnosis to systemic metastasis was 2.1 years and the mean latency between the radiologic diagnosis of the metastases and death was 299 days. Metastases were recorded in several organ systems in most of the cases, and at least two separate metastatic sites in 63% of the cases. Metastatic spread was noted in 60% of the cases in distant lymph nodes. Liver and lungs were the most affected solid organs. Systemic metastasis in MCC has no predilection site, basically every organ system can be involved. Most of the systemic metastases were recorded during the first two years after the MCC diagnosis.


IκB-α: At the crossroad between oncogenic and tumor-suppressive signals.
Nuclear factor κB (NF-κB) is an essential component of tumorigenesis and resistance to cancer treatments. NFKB inhibitor α (IκB-α) acts as a negative regulator of the classical NF-κB pathway through its ability to maintain the presence of NF-κB in the cytoplasm. However, IκB-α is also able to form a complex with tumor protein p53, promoting its inactivation. Recently, we demonstrated that IκB-α is able to mediate p53 nuclear exclusion and inactivation in chronic myeloid leukemia, indicating that IκB-α can modulate either oncogenic or tumor-suppressive functions, with important implications for cancer treatment. The present review describes the role of IκB-α in cancer pathogenesis, with particular attention to hematological cancers, and highlights the involvement of IκB-α in the regulation of p53 tumor-suppressive functions.


Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn's disease: a pilot study.
The differential diagnosis of ulcerative colitis from Crohn's disease is of pivotal importance for the management of inflammatory bowel diseases, as both entities involve specific therapeutic management strategies. Confocal laser endomicroscopy (CLE) allows on-demand, in vivo characterization of architectural and cellular details during endoscopy. The aim of this study was to assess the efficacy of CLE to differentiate between ulcerative colitis and Crohn's disease. This was a prospective study involving consecutive patients with a well-established diagnosis of ulcerative colitis or Crohn's disease who underwent colonoscopy with fluorescein-aided confocal imaging. Overall, 79 patients were included (40 Crohn's disease, 39 ulcerative colitis). CLE findings in patients with Crohn's disease, showed significantly more discontinuous inflammation (87.5 % vs. 5.1 %), focal cryptitis (75.0 % vs. 12.8 %), and discontinuous crypt architectural abnormality (87.5 % vs. 10.3 %) than in ulcerative colitis (P < 0.0001). Conversely, ulcerative colitis was associated with severe, widespread crypt distortion (87.2 % vs. 17.5 % in Crohn's disease), decreased crypt density (79.5 % vs. 22.5 %), and frankly irregular surface (89.7 % vs. 17.5 %; P < 0.0001 for all comparisons). Statistically significant differences were not seen for heavy, diffuse lamina propria cell increase or mucin preservation. No granulomas were visible. Based on these findings, a CLE scoring system was developed that revealed excellent accuracy (93.7 %) when compared with the historical clinical diagnosis and the histopathological gold standard. CLE could visualize several disease-specific microscopic features, which are conventionally used in standard histopathology to differentiate between ulcerative colitis and Crohn's disease. However, because of the limited penetration depth of CLE, submucosal details or granulomas were not visible. The new scoring system may allow in vivo diagnosis of ulcerative colitis or Crohn's disease. Trial registered at ClinicalTrials.gov: NCT 02238665.


UV radiation transmittance: regular clothing versus sun-protective clothing.
There are many clothing options available for patients who are interested in limiting their exposure to UV radiation; however, these options can be confusing for patients. For dermatologists, there is limited clinical data regarding the advantages, if any, of sun-protective clothing. In this study, we examined the UV radiation transmittance of regular clothing versus sun-protective clothing. We found that regular clothing may match or even exceed sun-protective clothing in blocking the transmittance of UV radiation. These data will help dermatologists better counsel their patients on clothing options for sun protection.


[Change in self-object differentiation in an eating disordered patient during inpatient therapy].
This paper is intended as a contribution to qualitative-quantitative research on the psychotherapeutic process. It reports on the course of a three-month inpatient psychosomatic treatment of a female patient with an eating disorder from the preferred point of view of psychoanalytically oriented individual therapy. Given the central role of the self-object relationship in women with eating disorders, changes that occur with regard to this aspect over the course of the therapy are recorded and described. In addition to the clinical perspective, the selected approach is based on a combination of methods, with an emphasis on the analysis of linguistic content using the Gottschalk-Gleser method, the Core Conflictual Relationship Theme method according to Luborsky and the projective procedure of Object Relations Technique according to Phillipson. In the course of treatment reveals changes in terms of reducing shame-anxiety and inwardly-directed aggressiveness as well as in the patient's object repproachement and to a more positive way of dealing with herself, all of which, on the whole, can be considered indicative of an increasing degree of self-object differentiation.


Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone.
A retrospective study of consecutive cases of massive carbamazepine poisoning treated in an intensive care unit during the period 1981-1991 was performed, mainly to determine whether serum carbamazepine levels were predictive of toxicity. Out of a total of 51 admissions with a diagnosis of carbamazepine self-poisoning, 28 (25 patients) were included. The reasons for exclusion were coingestion of other drugs (11 cases), incorrect diagnosis or inadequate information (6 cases), a peak observed serum concentration of carbamazepine below 76 mumol/L [18 mg/L] (4 cases), and lack of any documented serum carbamazepine assay (2 cases). The peak serum concentrations ranged from 78 to 285 mumol/L [18.4 to 67.4 mg/L]. It was found that serum levels equal to or above 170 mumol/L [40 mg/L] were significantly associated with an increased risk of serious complications such as coma, seizures, respiratory failure and cardiac conduction defects. In 60% of the 10 patients with a serum level > or = 170 mumol/L at least two of these symptoms occurred, in 50% at least three, and in 40% all four. There were two fatalities. Among the 16 patients (18 admissions) with a serum carbamazepine concentration below 170 mumol/L, only one was comatose and none had any of the other severe symptoms. It is concluded that serum carbamazepine levels accurately predict the severity of toxicity in massive carbamazepine poisoning in adults.


Epicardial placement of human placental membrane protects from heart injury in a swine model of myocardial infarction.
Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood-flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective strategies remain limited to prevent or attenuate IRI. We hypothesized that epicardial placement of human placental amnion/chorion (HPAC) grafts will protect against IRI. Using a clinically relevant model of IRI, swine were subjected to 45 min percutaneous ischemia followed with (MI + HPAC, n = 3) or without (MI only, n = 3) HPAC. Cardiac function was assessed by echocardiography, and regional punch biopsies were collected 14 days post-operatively. A deep phenotyping approach was implemented by using histological interrogation and incorporating global proteomics and transcriptomics in nonischemic, ischemic, and border zone biopsies. Our results established HPAC limited the extent of cardiac injury by 50% (11.0 ± 2.0% vs. 22.0 ± 3.0%, p = 0.039) and preserved ejection fraction in HPAC-treated swine (46.8 ± 2.7% vs. 35.8 ± 4.5%, p = 0.014). We present comprehensive transcriptome and proteome profiles of infarct (IZ), border (BZ), and remote (RZ) zone punch biopsies from swine myocardium during the proliferative cardiac repair phase 14 days post-MI. Both HPAC-treated and untreated tissues showed regional dynamic responses, whereas only HPAC-treated IZ revealed active immune and extracellular matrix remodeling. Decreased endoplasmic reticulum (ER)-dependent protein secretion and increased antiapoptotic and anti-inflammatory responses were measured in HPAC-treated biopsies. We provide quantitative evidence HPAC reduced cardiac injury from MI in a preclinical swine model, establishing a potential new therapeutic strategy for IRI. Minimizing the impact of MI remains a central clinical challenge. We present a new strategy to attenuate post-MI cardiac injury using HPAC in a swine model of IRI. Placement of HPAC membrane on the heart following MI minimizes ischemic damage, preserves cardiac function, and promotes anti-inflammatory signaling pathways.


Group psychotherapy for patients with coronary heart disease.
Group therapy with cardiac patients is a relatively new specialty. The field is supported by a substantial epidemiological and experimental literature demonstrating links between heart and mind. There are several clinical trials that have demonstrated less morbidity, improved quality of life, and, to some extent, lower mortality for patients who have received psychosocial intervention, generally group therapy, compared to control patients. Different theoretical orientations and a small number of clinical techniques have been developed to help cardiac patients make an adjustment to heart-healthy living. This article provides a brief review of the literature in cardiac psychology, suggestions for developing a psychotherapy practice specialty with cardiac patients, techniques for treating these patients, and conclusions by a psychologist-cardiologist team that has been active in this area for more than a decade.


Expanding the synthesis of a library of potent glucuronic acid glycodendrons for Dengue virus inhibition.
Multivalent glycodendrons are valuable tools to mimic many structural and functional features of cell-surface glycoconjugates and its focal position scaffolds represent important components to increase specificity and affinity. Previous work in our group described the preparation of a tetravalent glucuronic acid dendron that binds with good affinity to Dengue virus envelope protein (KD = 22 μM). Herein, the chemical synthesis and binding analysis of a new library of potent glucuronic acid dendrons bearing different functional group at the focal position and different level of multivalency are described. Their chemical synthesis was performed sequentially in three stages and with good yields. Namely a) the chemical synthesis of the oligo and polyalkynyl scaffolds, b) assembling with fully protected glucuronic acid-based azide units by using a microwave assisted copper-catalysed azide-alkyne cycloaddition reaction and c) sequential deprotection of hydroxyl and carboxylic acid groups. Surface Plasmon Resonance studies have demonstrated that the valency and the focal position functional group exert influence on the interaction with Dengue virus envelope protein. Molecular modelling studies were carried out in order to understand the binding observed. This work reports an efficient glycodendrons chemical synthesis that provides appropriate focal position functional group and multivalence, that offer an easy and versatile strategy to find new active compounds against Dengue virus.


Intravoxel incoherent motion diffusion-weighted MR imaging of breast cancer at 3.0 tesla: Comparison of different curve-fitting methods.
To compare three different curve-fitting methods for intravoxel incoherent motion (IVIM) analysis in breast cancer. Diffusion-weighted imaging was acquired in 30 patients with breast cancer using seven b-values (0-800 s/mm(2) ). Three curve-fitting methods were used for biexponential IVIM analysis: a. Direct estimation of D (diffusion coefficient), D* (pseudodiffusion coefficient) and f (perfusion fraction) (Method 1), b. Estimation of D first and then D* and f (Method 2), c. Estimation of D and f first and then D* (Method 3). Goodness-of-fit, parameter precision (coefficient of variance [CV]), parameter difference and correlation with relative enhancement ratio (RER) and initial area under the curve (IAUC) from dynamic contrast-enhanced (DCE) MRI of the three methods were determined and compared. Among the three biexponential methods, Method 1 best described most of the pixels (63.20% based on R(2) ; 44.52% based on Akaike Information Criteria). The CV of D calculated from Method 2/3 (14.95%/13.90%), the CV of D* from Method 2 (77.04%) and the CV of f from Method 3 (80.87%) were the lowest among the three methods. Significant difference was observed for each IVIM-derived parameter calculated from all the three methods (P = 0.000-0.005). Only the perfusion-related f value calculated from Method 2 was correlated with RER (r = 0.548; P = 0.002) or IAUC (r = 0.561; P = 0.001). IVIM-derived parameters differ depending on the calculation methods. The two-step fitting method with D value estimation first was correlated with DCE MRI perfusion.


Styrylbenzoazole derivatives for imaging of prion plaques and treatment of transmissible spongiform encephalopathies.
Recent prevalence of acquired forms of transmissible spongiform encephalopathies (TSEs) has urged the development of early diagnostic measures as well as therapeutic interventions. To extend our previous findings on the value of amyloid imaging probes for these purposes, styrylbenzoazole derivatives with better permeability of blood-brain barrier (BBB) were developed and analyzed in this study. The new styrylbenzoazole compounds clearly labeled prion protein (PrP) plaques in brain specimens from human TSE in a manner irrespective of pathogen strain, and a representative compound BF-168 detected abnormal PrP aggregates in the brain of TSE-infected mice when the probe was injected intravenously. On the other hand, most of the compounds inhibited abnormal PrP formation in TSE-infected cells with IC50 values in the nanomolar range, indicating that they represent one of the most potent classes of inhibitor ever reported. BF-168 prolonged the lives of mice infected intracerebrally with TSE when the compound was given intravenously at the preclinical stage. The new compounds, however, failed to detect synaptic PrP deposition and to show pathogen-independent therapeutic efficacy, similar to the amyloid imaging probes we previously reported. The compounds were BBB permeable and non-toxic at doses for imaging and treatment; therefore, they are expected to be of practical use in human TSE.


Sudden infant death syndrome: an unrecognized killer in developing countries.
Sudden infant death syndrome (SIDS) is defined as the sudden unexpected death of an infant <1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. SIDS contributes to infant mortality and resulted in ∼15,000 deaths globally in 2013. Most of the risk factors of SIDS are common in developing countries; yet, there has been little interest in SIDS by researchers in Africa. This review looks at the extent of the attention given to SIDS in a developing country like Nigeria, and factors responsible for the scarce data concerning this significant cause of mortality.


Functional Nano-Coating Materials by Michael Addition and Ring-opening Polymerization: Reactivity, Molecular Architecture and Refractive index.
Understanding the molecular interaction and morphology of organic-inorganic hybrid materials is an important and fundamental assignment to develop novel high-performance materials. In this work, we developed two types of hybrid coating materials by using different silane coupling agents via Michael addition reaction and ring-opening polymerization. The changes in molecular interaction and morphology of the hybrid coatings due to chemical composition and curing temperature were studied by electron microscopy, spectroscopy and solid state 29Si nuclear magnetic resonance analysis. Fundamental differences were observed in HYBRID I and HYBRID II coatings during the nucleation stage that was dependent on the curing temperature. Higher curing temperature of the hybrid coatings resulted in improved uniformity and greater crystallinity of dispersed phases, and better control of the morphology compared with coatings cured at lower temperatures. The higher curing temperature provided more consistent nucleation sites for the growth of larger nanostructures of desired characteristics (e.g., size and surface features). There is great flexibility in synthesizingg these hybrid materials where different structure and morphology can be achieved to produce materials whose applications can range from adhesives to protective coatings. Refractive index results revealed that HYBRID I (90 °C) coating showed higher refractive index than HYBRID II (90 °C) coating.


Multicenter case series of indolent small/medium-sized CD8+ lymphoid proliferations with predilection for the ear and face.
We report 7 cases of a CD8 lymphoid proliferation of the ear and face with a cytotoxic T-cell phenotype, but an indolent clinical course. All patients presented with stable or slowly growing asymptomatic lesions on the ear, nose, or lower eyelid. Histopathology showed a dense diffuse dermal infiltrate of small- to medium-sized atypical lymphocytes without destructive features. The lymphocytes were positive for CD3, CD8, β-F1, and TIA-1 and negative for CD4, CD30, CD56, granzyme B, and PD-1. Of note, the proliferation index was low in available cases. All patients remained in complete remission at median follow-up of 14 months regardless of treatment modality. Staging was negative for extracutaneous disease in all patients. The clinically indolent behavior and histopathologic phenotype together with a low proliferation index (10%-15%) emphasize the importance of accurate diagnosis and appropriate clinical management to avoid overtreatment and complications of therapy.


Open book tests: assessment of academic learning in clerkships.
An examination of an open-book testing approach in a family medicine clerkship seeks to determine whether this method more closely mirrors the discipline of family medicine, where practitioners refer daily to written resource materials in order to make clinical decisions without compromising the learning and assessment process. Student scores on the multiple-choice test were analysed by year, by quarter and by site using ANOVA. Students in the experimental site were interviewed to determine preparation style, use of text during test, as well as attitudes toward open-book testing. Analysis of variance showed that the interaction of site and year was significant at p = 0.03. The mean score of 88.2 for Maine students in 2002 was significantly different from the other three mean scores. The desired qualitative outcomes of the intervention were confirmed: reducing the anxiety of students, wider reading of the textbook, knowing the structure of the textbook as a learning resource, and deeper understanding of concepts and principles rather than time spent on memorization. While the difference in scores did reach statistical significance, it is important to note that the difference in mean score was only four points on a 100-point scale. Given the percentage of the total grade represented by the test score, it is unlikely that this difference represents any real difference in grade for students in Maine compared with Vermont. The students appeared to approach the textbook and therefore, perhaps, the body of knowledge as a whole with the orientation of a generalist. The MMC Clerkship Director recommended the implementation of the open-book approach to the Family Practice clerkship at all sites and the University of Vermont Medical School accepted the proposal. This recommendation supports advising students on the preparation for an open-book test and on tactics for the best use of the textbook during the test.


Unified and pluralistic ideals for data sharing and reuse in biodiversity.
How should billions of species observations worldwide be shared and made reusable? Many biodiversity scientists assume the ideal solution is to standardize all datasets according to a single, universal classification and aggregate them into a centralized, global repository. This ideal has known practical and theoretical limitations, however, which justifies investigating alternatives. To support better community deliberation and normative evaluation, we develop a novel conceptual framework showing how different organizational models, regulative ideals and heuristic strategies are combined to form shared infrastructures supporting data reuse. The framework is anchored in a general definition of data pooling as an activity of making a taxonomically standardized body of information available for community reuse via digital infrastructure. We describe and illustrate unified and pluralistic ideals for biodiversity data pooling and show how communities may advance toward these ideals using different heuristic strategies. We present evidence for the strengths and limitations of the unification and pluralistic ideals based on systemic relationships of power, responsibility and benefit they establish among stakeholders, and we conclude the pluralistic ideal is better suited for biodiversity data.


Eosinophilic cystitis with recurrent urinary retention: case report.
Eosinophilic cystitis is a rare inflammatory disease of the bladder whose origin, pathogenesis, and treatment are unknown. Frequency, dysuria, and hematuria are frequent symptoms. Here, we report a rare occurrence of recurrent urinary retention and repetitive catheterization. A 67-year-old male presented with acute urinary retention and intermittent gross hematuria of 2 weeks duration. Urethral catheterization followed by a trial without catheter, was successful. Complete blood count showed presence of eosinophils (eosinophilia) and computed tomography of kidneys, ureter and bladder with contrast showed thickened bladder wall and small prostate. Cystoscopy revealed an erythematous lesion over the anterior wall. The rest of the mucosa was normal. Transurethral biopsies of the lesion were performed and histologic examination showed features of eosinophilic cystitis. Despite multiple medication regimens containing corticosteroids and antihistamines, he presented with recurrent urinary retention, approximately once every month. After 6 months, he was started on bethanechol, which led to no catheterization for up to 2 years. To the best of our knowledge, this is the first report on the successful use of bethanechol as a treatment for eosinophilic cystitis with recurrent urinary retention.


Determination of serum bactericidal activity against Escherichia coli by an automated photometric method.
The resistance of gram-negative bacteria to complement-mediated serum activity is supposedly an important virulence factor. However, the lack of standardization in the methods used to determine serum activity and the many definitions applied make the comparisons between studies very difficult. We developed a rapid photometric method that we compared with a classical killing one. Escherichia coli in the exponential phase of growth in brain heart infusion broth (final inoculum, 10(7) CFU/ml) at 35 degrees C was added to 50% human serum in Veronal buffer. Viable counts and automatic recording of the variations in the optical densities were obtained for 40 E. coli strains isolated from the stools of healthy adults. With the viable count method, 17 (42.5%) were susceptible (at least a 1 log CFU/ml decrease), 17 (42.5%) were resistant (a 0.6 log CFU/ml increase), 4 (10%) were intermediate (poorly growing inoculum or a decrease of less than 1 log CFU/ml), and 2 could not be classified (nonreproducible results). Agreement between both methods was observed for 87.5% of the stool strains. Eight reference strains of known susceptibilities were classified identically by both methods, leading to a final concordance rate of 89.6%. A total of 129 blood isolates were tested by the photometric method: 64 (49.6%) were resistant, 50 (38.8%) were susceptible 5 (3.9%) showed early regrowth, and 10 (7.7%) were not perfectly reproducible. Of these 129 blood isolates, 5 were also tested by the killing method: 37 (49%) were resistant, 32 (43%) were susceptible, and 6 (8%) were intermediate. The concordance rate between both assays was 89% for the blood isolates; when the minor discordances were ruled out, it was 97%. This automated method could be a useful screening tool for detecting resistance to serum in clinical trials and for studying the in vitro variations of this property.


Stoma care.
Without doubt a most, if not the most, spectacular advance in the surgery of the colon and rectum in the last decade has been the vastly improved management of abdominal stomas and fistulas. This has been accomplished by a re-organisation of stoma care, aceptance by surgeons of the need to site their stomas with more precision and better apparatus.


Multimodal Therapy of Squamous Cell Carcinoma of the Anus With Distant Metastasis: A Single-Institution Experience.
Because of the rarity of the condition, studies concerning the management of patients with squamous cell carcinoma of the anus with distant metastasis are scarce. The available studies indicate poor outcomes with exclusive chemotherapy. Our aim was to evaluate the impact of multidisciplinary treatment on overall survival among patients presenting with metastatic squamous cell carcinoma of the anus. This was a retrospective study. The study was conducted at a single French institution between 2000 and 2014. Consecutive patients with histologically proven, newly diagnosed, or recurrent metastatic squamous cell carcinoma of the anus were included. Study interventions included multimodal therapy combining systemic chemotherapy and local ablative treatment to remove all metastases through surgery, radiofrequency ablation, or radiotherapy. The primary outcome measure was overall survival. Fifty patients (median age, 62 years; men/women: 8/42) fulfilled the inclusion criteria, and 39 were available for Response Evaluation Criteria in Solid Tumors. Forty had metastatic relapse after previous treatment of localized disease, and 10 presented with synchronous metastasis. P16 status was not available. Patients received at least 1 chemotherapy regimen, including 5-fluorouracil-mitomycin C (n = 22), cisplatin-5-fluorouracil (n = 20), or 5-fluorouracil alone (n = 3). Thirteen also had surgical metastasectomy, 11 had radiotherapy, and 6 had radiofrequency ablation. Median overall survival was 20.0 months (95% CI, 18.2-21.8 mo), and median time to failure of strategy was 6.0 months (95% CI, 2.9-9.1 mo). Overall response rate was 56% (95% CI, 40%-73%). Outcomes from the 5-fluorouracil-mitomycin C and cisplatin regimens did not statistically differ. Patients treated with multimodal therapy had a median overall survival of 22.0 months (95% CI, 15.3-28.6 mo) versus 13.0 months (95% CI, 9.5-16.5 mo; p = 0.002). Median time to failure of strategy was 10.0 months (95% CI, 4.2-15.7 mo) versus 5.0 months (95% CI, 2.8-7.2; p = 0.007). After 2 years, 40% of patients with multimodal treatment and 20% of those without ablative treatment were alive. This study is limited by its retrospective design and modest sample size. Stage IV squamous cell carcinoma of the anus outcomes are poor, but first-line chemotherapy can enable good response rates. Other treatment modalities, including surgery, radiotherapy, and thermoablation, should be considered, because they may provide a survival advantage. See Video Abstract at http://links.lww.com/DCR/A336.


[Epidemiology and strategy for the control of chronic respiratory diseases].
The conditions of tertiary prevention of chronic bronchitis are determined by prevalence, number of cases of inability to work, time of disease periods and age-depending mortality. An age-specific increase could be proved for all parameters. The critical age-line is about the 50th year of age. 75% of the bronchitis patients under medical care are older than 50 years of age. Measure of care ought to be concentrated on the time before the 50th year of age and on cases of risk. By an earlier beginning of medical care it is possible to increase the efficiency of tertiary prevention.