[Somatostatin analogs in oncology].
Somatostatin octapeptide analogues have a longer half-life and are more potent than natural somatostatin (SS-14). Somatostatin analogues are presently approved for the treatment of gastrointestinal (GI) endocrine cancers such as carcinoids, vipomas and glucagonomas. They are also effective in the treatment of inoperable or relapsing acromegaly. Although symptomatic relief is marked and rapidly induced, the inhibitory effect on tumor growth is modest. However, prolonged stabilizations are frequent. Somatostatin analogues may have wider therapeutic indications. Somatostatin octapeptide analogues are also known to interact with growth factors such as epidermal growth factor and insulin-like growth factor, and have shown cytostatic activity in vitro and in vivo in various experimental models of breast, prostate, lung and GI cancers. Neuroendocrine tumors often express somatostatin receptors. Labelled analogues may be useful for tumor assessment and for the prediction of tumor response to therapy. The role of somatostatin analogues in the treatment of the most frequent cancers is currently under investigation.


Accidental quinidine poisoning in two children.
Two cases of acute accidental quinidine poisioning in two children are presented. Both cases are characterized by the same ECG abnormalities consisting of rhythm disorders and AV and intraventricular conduction defects. It is suggested that there is a causal relationship between the electrophysiologic cardiac effects of quinidine and the ECG abnormalities observed. Both patients were successfully treated by continuous intravenous infusion of a hypertonic sodium chloride solution and lidocaine.


Genomic Knockout of Endogenous Canine P-Glycoprotein in Wild-Type, Human P-Glycoprotein and Human BCRP Transfected MDCKII Cell Lines by Zinc Finger Nucleases.
To investigate whether it is possible to specifically suppress the expression and function of endogenous canine P-glycoprotein (cPgp) in Madin-Darby canine kidney type II cells (MDCKII) transfected with hPGP and breast cancer resistance protein (hBCRP) by zinc finger nuclease (ZFN) producing sequence specific DNA double strand breaks. Wild-type, hPGP-transfected, and hBCRP-transfected MDCKII cells were transfected with ZFN targeting for cPgp. Net efflux ratios (NER) of Pgp and Bcrp substrates were determined by dividing efflux ratios (basal-to-apical / apical-to-basal) in over-expressing cell monolayers by those in wild-type ones. From ZFN-transfected cells, cell populations (ko-cells) showing knockout of cPgp were selected based on genotyping by PCR. qRT-PCR analysis showed the significant knock-downs of cPgp and interestingly also cMrp2 expressions. Specific knock-downs of protein expression for cPgp were shown by western blotting and quantitative targeted absolute proteomics. Endogenous canine Bcrp proteins were not detected. For PGP-transfected cells, NERs of 5 Pgp substrates in ko-cells were significantly greater than those in parental cells not transfected with ZFN. Similar result was obtained for BCRP-transfected cells with a dual Pgp and Bcrp substrate. Specific efflux mediated by hPGP or hBCRP can be determined with MDCKII cells where cPgp has been knocked out by ZFN.


[Benign tumors of the esophagus and stomach].
From the tumors of the oesophagus studied, 30% were found to be benign. They occurred in a ratio of 2:1 predominantly in men with an average age of 37,1 years compared to 52,5 years in women. The symptoms were unspecific and the prognosis was quo ad sanationem very good. Only in one case did a neurofibroma relapse explosively with in 4 months and was already inoperable at the time, when the new diagnosis was made. The percent of benign stomach tumors amounted to 2,6%. Tumors of the mucous tissue behaved differently than the neurogenic and mesenchymal ones. The former became noticeable mainly due to epigastric complaints, the latter due to haemorrhages. Epithelial tumors occurred, with a ratio of 2:1, more often in women, but without any difference in age. Mesenchymal and neurogenic tumors occurred in almost the same sex ratio, but at an average age, which was 18 years higher in women. Solitary stomach polypi can mostly be removed endoscopically, whilst all other benign oesophagus and stomach tumors must be removed by operation due to the symptoms and the dignity of the tumor, which is seldom clear.


Spontaneous occlusion of a spinal arteriovenous malformation: is treatment always necessary?
Knowledge of spinal cord arteriovenous malformations (AVMs) has recently been improved by studies on pathophysiology, neuroimaging, and genetic data. Nevertheless, the natural history of these lesions remains poorly understood. The authors present the case of an angiographic regression of a nidal-type spinal AVM at T-12 to L-1 in a 46-year-old woman with no risk factors. The natural course of untreated lesions is reviewed and discussed. To the best of the authors' knowledge, this is the first study that reports an angiographically proven complete spontaneous occlusion of a spinal AVM.


The Ex Vivo Colon Organ Culture and Its Use in Antimicrobial Host Defense Studies.
The intestine displays an architecture of repetitive crypt structures consisting of different types of epithelial cells, lamina propia containing immune cells, and stroma. All of these heterogeneous cells contribute to intestinal homeostasis and participate in antimicrobial host defense. Therefore, identifying a surrogate model for studying immune response and antimicrobial activity of the intestine in an in vitro setting is extremely challenging. In vitro studies using immortalized intestinal epithelial cell lines or even primary crypt organoid culture do not represent the exact physiology of normal intestine and its microenvironment. Here, we discuss a method of culturing mouse colon tissue in a culture dish and how this ex vivo organ culture system can be implemented in studies related to antimicrobial host defense responses. In representative experiments, we showed that colons in organ culture express antimicrobial peptides in response to exogenous IL-1β and IL-18. Further, the antimicrobial effector molecules produced by the colon tissues in the organ culture efficiently kill Escherichia coli in vitro. This approach, therefore, can be utilized to dissect the role of pathogen- and danger-associated molecular patterns and their cellular receptors in regulating intestinal innate immune responses and antimicrobial host defense responses.


Production of immunoreactive growth hormone by mononuclear leukocytes.
In the present study, we evaluated whether mononuclear leukocytes could synthesize and secrete growth hormone (GH) in vitro. By using RNA slot blot analysis, we detected maximum spontaneous levels of specific GH mRNA in the cytoplasm of rat leukocytes after a 4-h incubation. Northern gel analysis demonstrated that the specific leukocyte GH RNA was polyadenylated and had a molecular mass of 1.0 kb. Further studies using immunofluorescence, antibody affinity chromatography, and Sephacryl gel filtration indicate that leukocytes secrete a high molecular weight (greater than 300,000) and a low molecular weight (approximately 22,000) immunoreactive GH (irGH). A substantial amount of the high molecular weight irGH can be converted to the lower molecular weight form after reduction with mercaptoethanol. The irGH appeared to be de novo synthesized because it could be radiolabeled with tritiated amino acids and its production could be blocked by previous incubation of leukocytes with cycloheximide. The replication of Nb2 rat node lymphoma cells was stimulated by affinity-purified human lymphocyte-derived irGH. The growth stimulation was blocked by specific antibodies to hGH. We conclude that lymphocytes produce an irGH that is similar to if not identical to pituitary GH in terms of bioactivity, antigenicity, and molecular weight. The findings demonstrate a potential regulatory loop between the immune and neuroendocrine tissues.


The intersectionality-based policy analysis framework: demonstrating utility through application to the pre-vaccine U.S. COVID-19 policy response.
Few guidelines exist for the development of socially responsible health policy, and frameworks that balance considerations of data, strategy, and equity are limited. The Intersectionality-Based Policy Analysis (IBPA) framework utilizes a structured questioning process to consider problems and policies, while applying guiding principles of equity, social justice, power, intersectionality, and diversity of knowledge and input. We apply the IBPA framework's guiding principles and questions to the pre-vaccine U.S. COVID-19 policy response. Results suggest the IBPA approach is a promising tool for integrating equity considerations in the development of policy solutions to urgent US public health challenges, including the COVID-19 pandemic. We found the IBPA framework particularly useful in differentiating between problems or policies and representations of problems or policies, and in considering the impacts of representations on different groups. The explicit inclusion of short-, medium- and long-term solutions is a reminder of the importance of holding a long-term vision of the equitable public health system we want while working towards immediate change.


Seizure incidence in 80,000 patient treatments with hyperbaric oxygen.
Hyperbaric oxygen treatment (HBOT) involves some risk of central nervous system (CNS) oxygen toxicity, which may be revealed by various signs and symptoms including seizures in patients breathing O2 at pressures of 2 ATA or higher. The aim of this study was to determine the incidence of such seizures in the Underwater and Hyperbaric Medicine Departments of two university hospitals. We retrospectively evaluated 80,679 patient-treatments for 9 clinical indications to determine the incidence of seizures attributable to CNS O2 toxicity. Because different protocols were used for HBOT, the treatments were studied in four groups according to the chamber type used and the medical facility at which it was located. Only 2 seizures were documented, yielding an incidence of 2.4 per 100,000 patient-treatments. Both cases occurred in a multiplace chamber pressurized to 2.4 ATA with O2 delivered by mask for three x 30 min with 5-min air breaks. The seizure incidence reported here is lower than other studies published in the literature. The delivery of O2 by mask rather than hood may be a factor. Nevertheless, it appears that the risk of seizures due to CNS O2 toxicity during HBOT is very low as long as appropriate exclusion criteria and treatment profiles are used.


Social networks and quality of life among female long-term colorectal cancer survivors.
The population of long-term colorectal cancer survivors in the United States continues to increase, but little is known about how they fare-physically, mentally, or socially-in the years after diagnosis. The current study examines female long-term colorectal cancer survivors' health-related quality of life (HRQoL) in relation to social networks. A population-based sample of female colorectal cancer survivors (n = 726) residing in Wisconsin was recontacted approximately 9 years after the initial diagnosis. Of 443 women who were alive in 1999, 307 women completed a follow-up questionnaire. Analysis was conducted on 259 participants who completed the Medical Outcomes Study Short Form 36 Health Status Survey and a modified version of Berkman and Syme's Social Network Index. Using multivariate analyses, HRQoL summary scores were tested for associations with individual and composite measures of social networks, including marital/partner status; number of children, relatives, and friends; and the frequency of religious and community participation. After adjusting for age, extent of disease at diagnosis, number of comorbidities, body mass, and education, HRQoL was similar to norms published for the general population. Individual social network measures (including the number of relatives and friends) and composite network measures (including network size, the number of ties seen at least once per month, and overall social connectedness) were associated positively with mental health. Social networks may have an important relation with HRQoL-particularly mental health-among female long-term colorectal cancer survivors. The results of this study should be of interest to those seeking to understand or improve HRQoL among this growing population.


Intra-Abdominal Hypertension Causes Bacterial Growth in Lungs: An Animal Study.
To study the effect of intra-abdominal hypertension (IAH) on the frequency of pneumonia with an experimental study, thirteen Sprague-Dawley rats were included. Eight out of thirteen animals were randomly assigned to receive 10 ml of benzalkonium chloride 0.2% (megacolon group) and five animals received 10 ml NaCl 0.9% (controls). Animals were anaesthetized by intramuscular delivery of ketamine. The incidence of positivity for bacteria lung tissue cultures and mesenteric lymph node cultures was assessed at the 21st day after animals' sacrification, or before in case of death. All megacolon group animals presented progressive increase of the abdomen and increased IAP (≥10 mmHg) whereas the frequency of their evacuations was almost eliminated. Controls presented normal evacuations, no sign of abdominal distention, and normal IAP. In megacolon group animals, there was evidence of significant amount of bacteria in lung cultures. In contrast, no bacteria were found in control animals.


Spin liquid state in an organic Mott insulator with a triangular lattice.
1H NMR and static susceptibility measurements have been performed in an organic Mott insulator with a nearly isotropic triangular lattice, kappa-(BEDT-TTF)2Cu2(CN)(3), which is a model system of frustrated quantum spins. The static susceptibility is described by the spin S=1/2 antiferromagnetic triangular-lattice Heisenberg model with the exchange constant J approximately 250 K. Regardless of the large magnetic interactions, the 1H NMR spectra show no indication of long-range magnetic ordering down to 32 mK, which is 4 orders of magnitude smaller than J. These results suggest that a quantum spin liquid state is realized in the close proximity of the superconducting state appearing under pressure.


Cement Mantle Thickness at the Bone Cement Interface in Total Knee Arthroplasty: Comparison of PS150 RP and LPS-Flex Knee Implants.
To analyze the thickness of cement mantle at the bone cement interface in knees with closed and open box designs in total knee arthroplasty (TKA). Eighty cases of TKA were performed from October 2013 to March 2014. The average age of the patients was 68.4 years. All patients were women and they were divided into two groups: group I with a closed box implant (PS150 RP, n=40) and group II with an open box implant (LPS-Flex, n=40). We measured the cement mantle thickness at the bone cement interface from the distal femur and proximal tibia. If the thickness was >1 mm, it was considered an outlier. The mean cement mantle thickness at the interface was 1.4 mm in the distal femur and 0.8 mm in the proximal tibia. The value exceed 1 mm in 40 cases (50%) in the distal femur and in 6 cases (7.5%) in the proximal tibia (p<0.001). The mean cement mantle thickness measured in the distal femur was 1.7 mm in group I and 1.0 mm in group II. The value exceed 1 mm in 32 cases (80%) in group I and in 8 cases (20%) in group II (p<0.000). The cement mantle at the interface was thicker in the knees with the closed box implant than those with the open box implant in TKA, especially in the distal femoral area. A thick cement mantle at the interface should be avoided because it affects the gap balance. In case of using a closed box implant in TKA, cementing should be performed with extra care.


Role of CD93 in Health and Disease.
CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies.


Peripheral and central effects of melatonin on blood pressure regulation.
The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology.


Genetic stability of a dengue vaccine based on chimeric yellow fever/dengue viruses.
A tetravalent dengue vaccine based on four live, attenuated, chimeric viruses (CYD1-4), constructed by replacing the genes coding for premembrane (prM) and envelope (E) proteins of the yellow fever (YF)-17D vaccine strain with those of the four serotypes of dengue virus, is in clinical phase III evaluation. We assessed the vaccine's genetic stability by fully sequencing each vaccine virus throughout the development and manufacturing process. The four viruses displayed complete genetic stability, with no change from premaster seed lots to bulk lots. When pursuing the virus growth beyond bulk lots, a few genetic variations were observed. Usually both the initial nucleotide and the new one persisted, and mutations appeared after a relatively high number of virus duplication cycles (65-200, depending on position). Variations were concentrated in the prM-E and non-structural (NS)4B regions. PrM-E variations had no impact on lysis-plaque size or neurovirulence in mice. None of the variations located in the YF-17D-derived genes corresponded with reversion to the wild-type Yellow Fever sequence. Variations in NS4B likely reflect virus adaptation to Vero cells growth. A low to undetectable viremia has been reported previously [1-3] in vaccinated non-human and human primates. Combined with the data reported here about the genetic stability of the vaccine strains, the probability of in vivo emergence of mutant viruses appears very low.


Optical spectroscopic studies of thermally coalesced single-walled carbon nanotubes.
Changes in the optical properties of thermally coalesced single-walled carbon nanotubes (SWCNTs) caused by heat treatment between 1300 and 2800 degrees C in argon, have been monitored using optical absorption and photoluminescence spectroscopy. For SWNTs heat treated at 1900 degrees C, we found a complete disapperance of small-diameter tubes (<1.0 nm) as well as the appearance of enlarged, defective tubes. The decreased sp2/sp3 ratio for tubes heat treated below 2100 degrees C suggests that adjacent small-diameter SWNTs transform into energetically stable larger-diameter SWNTs by the presence of structural non sp2 defects.


Liver Transplantation in Liver Cirrhosis Patients Accompanied by Portal Vein Thrombosis.
Benign portal vein thrombosis (PVT) is a challenging complication of an otherwise successful liver transplantation. PVT is caused by various conditions and results in pathologic hemodynamics of hepatofugal diversion of porto-mesenteric blood flow. Thus, adequate restoration of portal blood flow to the liver graft is a major concern when trying to achieve successful liver transplantation in patients with PVT. This letter describes the surgical view point of PVT in liver transplantation.


High-dose etoposide formulations do not saturate intestinal P-glycoprotein: Development, stability, and pharmacokinetics in Sprague-Dawley rats.
It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide's solubility approximately 100 times (16 mg mL-1) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC0-∞ of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg-1), AUC0-∞ and Cmax were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg-1. A single oral dose of 20 mg kg-1 zosuquidar followed by 20 mg kg-1 oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.


DEVELOPMENT AND VALIDATION OF QUANTITATIVE PCR ASSAYS TO MEASURE CYTOKINE TRANSCRIPT LEVELS IN THE FLORIDA MANATEE ( TRICHECHUS MANATUS LATIROSTRIS).
Cytokines have important roles in the mammalian response to viral and bacterial infections, trauma, and wound healing. Because of early cytokine production after physiologic stresses, the regulation of messenger RNA (mRNA) transcripts can be used to assess immunologic responses before changes in protein production. To detect and assess early immune changes in endangered Florida manatees ( Trichechus manatus latirostris), we developed and validated a panel of quantitative PCR assays to measure mRNA transcription levels for the cytokines interferon (IFN)-γ; interleukin (IL)-2, -6, and -10; tumor necrosis factor-α; and the housekeeping genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin (reference genes). Assays were successfully validated using blood samples from free-ranging, apparently healthy manatees from the east and west coasts of central Florida, US. No cytokine or housekeeping gene transcription levels were significantly different among age classes or sexes. However, the transcription levels for GAPDH, IL-2, IL-6, and IFN-γ were significantly higher ( P<0.05) in manatees from the east coast of Florida than they were from those from the west coast. We found IL-10 and β-actin to be consistent between sites and identified β-actin as a good candidate for use as a reference gene in future studies. Our assays can aid in the investigation of manatee immune response to physical trauma and novel or ongoing environmental stressors.


[Myasthenia gravis with anti-acetylcholine receptor antibody or anti-muscle specific kinase antibody].
Patients with myasthenia gravis (MG) are divided into 3 groups: anti-acetylcholine receptor antibody-positive MG (AChR MG), anti-muscle specific kinase antibody-positive MG (MuSK MG), and AChR-and MuSK-negative MG (double seronegative MG; double SNMG). A recent study on the detection of low-affinity antibodies binding to AChR showed the presence of AChR antibodies in about 70% of double SNMG patients. There is accumulating evidence that double SNMG patients are similar to AChR-MG patients with respect to clinical features and thymic pathology. Since most MG patients are thought to belong to the AChR-MG or MuSK-MG group of patients, this article reviews the pathophysiology, clinical features, and treatments in these 2 groups of MG patients. The pathophysiology of AChR-MG is closely related to the abnormal thymic pathology, such as thymic hyperplasia or presence of thymoma, and thy(mo)mectomy is recommended in patients with generalized AChR-MG. On the contrary, little thymic abnormality in patients with MuSK-MG discourages thymectomy; however, MuSK-MG patients do respond to thymectomy and therefore studies to define the indications of thymectomy in MuSK-MG patients are required. The responses to cholinesterase inhibitors are poor in patients with MuSK-MG, and these patients tend to show hyperactivity to the Tensilon test, such as fasciculation of facial muscles and stuffy sensation in the throat. The adverse responses to a small dose of intravenous edrophonium chloride injection may support the clinical diagnosis of MuSK-MG. Further, only small doses of acetylcholinesterase inhibitors are administered to patients with MuSK-MG in order to avoid cholinergic hyperactivity. In general, both types of MG patients respond well to treatments with immunosuppressants, including steroids, but some patients with MuSK-MG show persistent bulbar symptoms.


Binding of C-reactive protein to the pneumococcal capsule or cell wall results in differential localization of C3 and stimulation of phagocytosis.
C-reactive protein (CRP) is a serum protein that shows rapid increases of as much as 1000-fold in concentration in response to infection, traumatic injury, or inflammation. CRP reacts with the phosphocholine moiety of pneumococcal cell wall C-polysaccharide, and this reaction can lead to complement activation in vitro and protection against pneumococcal infection in vivo. We have previously studied the chemiluminescence response of human neutrophils to Streptococcus pneumoniae as a measure of in vitro opsonophagocytosis by CRP and complement. CRP in the presence of complement was an effective opsonin for S. pneumoniae serotype 27 (Pn27), but not for serotypes 3 or 6. Because Pn27 differs from most serotypes of S. pneumoniae in containing phosphocholine in its capsular polysaccharide, we have determined the sites of CRP and C3 fixation to Pn27 and S. pneumoniae serotype 4 (Pn4), and related these to the ability of CRP and complement to opsonize these serotypes in vitro. By using a chemiluminescence (CL) assay to measure opsonophagocytosis, CRP was shown to enhance the response of human neutrophils and monocytes to Pn27 in the presence of normal human serum. The CL response of neutrophils and monocytes to Pn4 was not affected by the addition of CRP to serum. The addition of anti-capsular antibody to Pn4 and Pn27 enhanced the CL responses of both neutrophils and monocytes to both bacteria. The localization of bound CRP and C3 on Pn4 and Pn27 was determined by immunoelectron microscopy. CRP bound to Pn4 only in the cell wall region and C3 was located in this area whether or not CRP was present. Anti-capsular antibody deposited C3 in the capsule of Pn4. In contrast, Pn27 bound CRP throughout the capsule and cell wall areas. C3 was deposited in the cell wall region of Pn27 by serum alone and in the cell wall region and capsule when CRP or anti-capsular antibody was present. Because C3 fixation to the capsule was consistently associated with enhanced responses by phagocytic cells, it appears that the site of CRP binding and subsequent complement activation may be critical in the opsonophagocytosis of S. pneumoniae. These findings extend the correlation between capsular C3 and opsonization to a nonimmune system. By using CRP and different pneumococcal serotypes we have shown that the same molecules that are effective in the stimulation of phagocytic cells when bound to the capsule are not effective when bound to the cell wall.


Hypofibrinolytic State in Subjects with Type 2 Diabetes Mellitus Aggravated by the Metabolic Syndrome before Clinical Manifestations of Atherothrombotic Disease.
Background. Metabolic and genetic factors induce plasminogen activator inhibitor type-1 (PAI-1) overexpression; higher PAI-1 levels decrease fibrinolysis and promote atherothrombosis. Aim. To assess PAI-1 antigen levels among subjects with type 2 diabetes mellitus (T2DM) plus Metabolic Syndrome (MetS) before clinical manifestations of atherothrombosis and the contribution of metabolic factors and 4G/5G polymorphism of PAI-1 gene on the variability of PAI-1. Methods. We conducted an observational, cross-sectional assay in a hospital in Mexico City from May 2010 to September 2011. MetS was defined by the International Diabetes Federation criteria. PAI-1 levels and 4G/5G polymorphism were determined by ELISA and PCR-RFLP analysis. Results. We enrolled 215 subjects with T2DM plus MetS and 307 controls. Subjects with T2DM plus MetS had higher PAI-1 levels than the reference group (58.4 ± 21 versus 49.9 ± 16 ng/mL, p = 0.026). A model with components of MetS explained only 12% of variability on PAI-1 levels (R2 = 0.12; p = 0.001), with β = 0.18 (p = 0.03) for hypertension, β = -0.16 (p = 0.05) for NL HDL-c, and β = 0.15 (p = 0.05) for NL triglycerides. Conclusion. Subjects with T2DM plus MetS have elevated PAI-1 levels before clinical manifestations of atherothrombotic disease. Metabolic factors have a more important contribution than 4G/5G polymorphism on PAI-1 plasma variability.


[Hematological study in 27 patients with myelodysplastic syndrome (MDS)].
The clinical, histologic, and cytogenetic features of myelodysplastic syndrome (MDS) were analyzed in 27 patients consisting of 21 males and 6 females (M: F ratio = 3.5:1) whose median age was 60.9 years. Analysis of the peripheral blood of the patients revealed pancytopenia (8 patients), bicytopenia (12), and cytopenia in one cell lineage (5). The patients had high serum iron value and low UIBC value. More than 20% of all erythroid cells in the bone marrow consisted of ringed sideroblasts in not only RARS patients but also RAEB, CMMoL, and RAEB-T patients. Morphological changes of the bone marrow cells were observed in patients with all types of MDS. Eighty percent and 60% of RAEB and RAEB-T patients, respectively, showed trilineage myelodysplasia. Chromosomal abnormalities were observed in 52% of MDS patients. The rate of leukemic transformation was high in RAEB, CMMoL, and RAEB-T patients.


Productive infection by B19 parvovirus of human erythroid bone marrow cells in vitro.
B19 parvovirus, the cause of fifth disease and transient aplastic crisis, has been successfully propagated in suspension cultures of human erythroid bone marrow cells obtained from patients with sickle cell disease and stimulated by erythropoietin. B19 inoculation in vitro resulted in a marked decline in identifiable erythroid cells over seven to nine days of incubation. Characteristic giant early erythroid cells were seen on Wright's-Giemsa stain of infected cultures. By in situ hybridization, 30% to 40% of erythroblasts were infected at 48 hours; a similar proportion of cells showed B19 capsid protein by immunofluorescence. B19 DNA was present in erythroblasts but not in the leukocyte fraction of bone marrow. B19 replication, as determined by Southern analysis, and B19 encapsidation, as determined by sensitivity of isolated cell fractions to DNase I, were restricted to the nuclei. B19 DNA was detectable in the nuclei from infected cultures beginning at 18 hours and in the supernatant at 32 hours; B19 genome copy number was estimated at about 25,000 to 30,000/infected cell at 48 hours. Recovery of virus depended on the multiplicity of infection (moi); at low moi, approximately 200x input virus was recovered from total cultures and 50x from the culture supernatants. Virus released into the supernatant was as infectious or more infectious than virus obtained from sera of infected patients. Human erythroid bone marrow culture represents a safe in vitro system for the elucidation of the cellular and molecular biology of the pathogenic B19 parvovirus.


Co-occurrence of Periodontitis and Diabetes-Related Complications.
Periodontitis is a common finding among people with diabetes mellitus (DM) and has been cited as a DM complication. Whether and how periodontitis relates to other diabetes-related complications has yet to be explored. This study aims to examine the clustering of periodontitis with other diabetes-related complications and explore pathways linking diabetes-related complications with common risk factors. Using data from participants with DM across 3 cycles of the National Health and Nutrition Examination Survey (NHANES) (n = 2,429), we modeled direct and indirect pathways from risk factors to diabetes-related complications, a latent construct comprising periodontitis, cardiovascular diseases, proteinuria, and hypertension. Covariates included age, sex, socioeconomic status (SES), smoking, physical activity, healthy diet, alcohol consumption, hemoglobin A1c (HbA1c), dyslipidemia, and body mass index (BMI). Sensitivity analyses were performed considering participants with overweight/obesity and restricting the sample to individuals without DM. Periodontitis clustered with other diabetes complications, forming a latent construct dubbed diabetes-related complications. In NHANES III, higher HbA1c levels and BMI, older age, healthy diet, and regular physical activity were directly associated with the latent variable diabetes-related complications. In addition, a healthy diet and BMI had a total effect on diabetes-related complications. Although sex, smoking, dyslipidemia, and SES demonstrated no direct effect on diabetes-related complications in NHANES III, a direct effect was observed using NHANES 2011-2014 cycles. Sensitivity analysis considering participants with overweight/obesity and without DM showed consistent results. Periodontal tissue breakdown seems to co-occur with multiple diabetes-related complications and may therefore serve as a valuable screening tool for other well-known diabetes-related complications.


[Urological investigation in women with stress incontinence prior and following anterior colporrhaphy and in control patients (author's transl)].
The pre-operative and post-operative findings in 56 patients with urinary stress incontinence are compared amongst each other and with the result of 24 continent control patients. The 56 patients were selected prospectively. The urethral closure pressure with stress and the stress quotient in urethral cystometry are significantly improved by the operations. The compliance as a cystometric criterium was significantly raised. The sizes of the angle in the urethrocystogram are at times significantly changed after operation. They are not lower than the values described in the literature. This shows good correlation with the results in the control groups, which have angles higher than those described in the literature. The time parameters of the uroflowmetry show prolongation after the anterior colporrhaphy. The times to the maximum, the waiting time, the urine flow time and the duration of micturition are longer. The mean volume of urine per second is not significantly changed. Our results are compared with other investigations. The findings in healthy continent women are considered to be possible parameters for a reference.


Photonic-assisted 2-D terahertz beam steering enabled by a LWA array monolithically integrated with a BFN.
A novel photonic-assisted 2-D Terahertz beam steering chip using only two tuning elements is presented. The chip is based on an array of three leaky wave antennas (LWAs) with a monolithically integrated beamforming network (BFN) on a 50 µm-thick indium phosphide substrate. The THz beam angle in elevation (E-plane) is controlled via optical frequency tuning using a tunable dual-wavelength laser. An optical delay line is used for azimuth (H-plane) beam control. The simulated beam scanning range is 92° in elevation for a frequency sweep from 0.23 THz to 0.33 THz and 69.18° in azimuth for a time delay of 3.6 ps. For the frequency range from 0.26 THz to 0.32 THz, it is confirmed experimentally that the THz beam scans from -12° to +33°, which is in good agreement with the numerical simulations. The beam direction in azimuth scans with a total angle of 39° when applying a delay difference of 1.68 ps. A good agreement is found between theoretically predicted and experimentally determined THz beam angles with a maximum angle deviation below 5°. The experimental scanning angles are limited due to the mechanical constraints of the on-wafer probes, the on-chip integrated transition and the bandwidth of the THz receiver LNA. The mechanical limitation will be overcome when using a packaged chip.


Increased self-diffusion of brain water in hydrocephalus measured by MR imaging.
We used MR imaging to measure the apparent brain water self-diffusion in 5 patients with normal pressure hydrocephalus (NPH), in 2 patients with high pressure hydrocephalus (HPH), and in 8 age-matched controls. In all patients with NPH significant elevations of the apparent diffusion coefficients (ADC) of brain water were found within periventricular white matter, in the corpus callosum, in the internal capsule, within cortical gray matter, and in cerebrospinal fluid, whereas normal ADCs were found within the basal ganglia. In 2 patients with HPH elevated ADCs were found most prominently within white matter, and in one patient reexamined one year after surgery, ADCs were unchanged in nearly all brain regions. The increased ADC values in hydrocephalus patients may be caused by factors such as changes in myelin-associated bound water, increased Virchow-Robin spaces, and increased extracellular brain water fraction. For further studies of brain water diffusion in hydrocephalus patients, echo-planar imaging techniques with imaging times of a few seconds may be valuable.


New depsidones and isoindolinones from the mangrove endophytic fungus Meyerozyma guilliermondii (HZ-Y2) isolated from the South China Sea.
Three new depsidones, botryorhodines E-G (1-3), and two new isoindolinones, meyeroguillines A and B (7 and 9), along with five known compounds were isolated from an endophytic fungus Meyerozyma guilliermondii, derived from the mangrove plant Kandelia obovata. Their structures were elucidated by 1D and 2D NMR spectroscopy and high resolution mass spectrometry (HREIMS). Compounds 1-6 exhibited strong α-glucosidase inhibitory activity with IC50 values ranging from 2.1 to 13.3 μM. Moreover, kinetic studies of compounds 2 and 6 showed that both of them were noncompetitive inhibitors of α-glucosidase.


Long-Term Outcomes of Acute Endovascular Thrombectomy: Tokyo/tama-Registry of Acute Endovascular Thrombectomy (TREAT).
Mechanical thrombectomy (MT) is the recommended treatment for patients with acute ischemic stroke due to large cerebral vessel occlusion (LVO). However, few studies have investigated long-term outcomes after MT. The aim of this study was to investigate functional outcomes at long-term follow-up (1 year after MT) in patients undergoing MT for anterior circulation LVO in real-world clinical practice. This was a retrospective and prospective observational study using data from TREAT (Tokyo/tama-Registry of Acute Endovascular Thrombectomy), a multicenter registry of MT for acute LVO in the Tokyo metropolitan area. All subjects emergently transferred and treated with MT from January 2015 to December 2018 were selected. Patients' baseline characteristics and stroke-related parameters were evaluated. The primary outcome was the modified Rankin Scale (mRS) score 1 year after MT. The secondary outcomes were risk factors for long-term good outcomes (mRS score 0-2); transfer system (stroke bypass vs. secondary transfer) was also evaluated as a potential factor associated with good long-term outcomes. A total of 162 cases (mean age 73.0 years, age range 30-97 years; 59.9% male) whose mRS scores at 1 year were obtained were analyzed. The median admission National Institutes of Health Stroke Scale (NIHSS) score was 17. Overall, 42.6% of the patients achieved functional independence at 1-year follow-up. Lower initial NIHSS score and mRS score 0-2 at 90 days were the independent predictors for good long-term outcomes. Stroke bypass was associated with a higher initial NIHSS score and mRS score 0 at 1 year. A significant number of patients experience a good long-term outcome after MT.


Correlation of Tumor Necrosis Factor-α -308G>A Polymorphism with Susceptibility, Clinical Manifestations, and Severity in Behçet Syndrome: Evidences from an Italian Genetic Case-Control Study.
To investigate the association between a functional drug-response tumor necrosis factor (TNF)α gene polymorphism (at the positions of -308; rs1800629; NG_007462.1:g.4682G>A) and both disease susceptibility and clinical manifestations in a cohort of 130 Italian patients with Behçet syndrome (BS). A group of 100 ethnically, age, and gender matched healthy controls (HC) was also recruited. Genotyping was performed using molecular (amplification and direct sequencing) and in silico methods. The genotype distribution of BS patients and HC underlined a lower percentage of wild-type GG genotype in BS patients versus HC (106/130 patients, 81.5% vs. 91/100 HC, 91%; p < 0.05), while the heterozygous genotype (GA) was identified in 24/130 patients (18.5%) versus 9/100 HC (9%) (p < 0.05). GA genotype was significantly associated with the disease (odds ratio = 2.29, 95% confidence interval 1.01-5.18). No significant association was recognized between the single nucleotide polymorphism (SNP) and the BS clinical manifestations, as well as with disease severity (Krause's index). We found statistically significant higher frequency of TNFα rs1800629 GA genotype in patients than in controls. No significant association was recognized between the polymorphism and the clinical parameters, as well as between the SNP and the disease severity. Our data need to be confirmed in larger cohort of patients and matched controls.


Early identification and cochlear implantation: critical factors for spoken language development.
Documentation is lacking regarding the ability of congenitally deaf children to attain age-appropriate spoken language skills using a cochlear implant, and how early implantation must occur if such development is to be possible. Spoken language data are presented for infants who underwent implantation at 18 months of age or younger. Additional data are used to compare outcomes among children who differed in age at implantation. Data collected at Carle Clinic and Foundation Hospital were reviewed for 47 consecutively implanted children ranging in age from 9 to 48 months at implantation. These data were analyzed and compared by age-at-implantation groupings for speech perception skills, communication mode, and spoken language abilities. The groups differed dramatically in abilities. The best outcomes occurred in children who underwent implantation at or before 18 months of age. Several of these infants demonstrated age-appropriate spoken language skills. We conclude that early implantation is desirable. Children who undergo implantation as infants may develop language skills commensurate with those of their hearing peers.


A physiological and behavioral system for hearing restoration with cochlear implants.
Cochlear implants are neuroprosthetic devices that provide hearing to deaf patients, although outcomes are highly variable even with prolonged training and use. The central auditory system must process cochlear implant signals, but it is unclear how neural circuits adapt-or fail to adapt-to such inputs. The knowledge of these mechanisms is required for development of next-generation neuroprosthetics that interface with existing neural circuits and enable synaptic plasticity to improve perceptual outcomes. Here, we describe a new system for cochlear implant insertion, stimulation, and behavioral training in rats. Animals were first ensured to have significant hearing loss via physiological and behavioral criteria. We developed a surgical approach for multichannel (2- or 8-channel) array insertion, comparable with implantation procedures and depth in humans. Peripheral and cortical responses to stimulation were used to program the implant objectively. Animals fitted with implants learned to use them for an auditory-dependent task that assesses frequency detection and recognition in a background of environmentally and self-generated noise and ceased responding appropriately to sounds when the implant was temporarily inactivated. This physiologically calibrated and behaviorally validated system provides a powerful opportunity to study the neural basis of neuroprosthetic device use and plasticity.


Discoveries and application of prostate-specific antigen, and some proposals to optimize prostate cancer screening.
The discoveries and application of prostate-specific antigen (PSA) have been much appreciated because PSA-based screening has saved millions of lives of prostate cancer (PCa) patients. Historically speaking, Flocks et al first identified antigenic properties in prostate tissue in 1960. Then, Barnes et al detected immunologic characteristics in prostatic fluid in 1963. Hara et al characterized γ-semino-protein in semen in 1966, and it has been proven to be identical to PSA. Subsequently, Ablin et al independently reported the presence of precipitation antigens in the prostate in 1970. Wang et al purified the PSA in 1979, and Kuriyama et al first applied an enzyme-linked immunosorbent assay for PSA in 1980. However, the positive predictive value with a cutoff figure of 4.0 ng/mL appeared substantially low (∼30%). There are overdiagnoses and overtreatments for latent/low-risk PCa. Controversies exist in the PCa mortality-reducing effects of PSA screening between the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. For optimizing PCa screening, PSA-related items may require the following: 1) adjustment of the cutoff values according to age, as well as setting limits to age and screening intervals; 2) improving test performance using doubling time, density, and ratio of free: total PSA; and 3) fostering active surveillance for low-risk PCa with monitoring by PSA value. Other items needing consideration may include the following: 1) examinations of cell proliferation and cell cycle markers in biopsy specimens; 2) independent quantification of Gleason grading; 3) developing ethnicity-specific staging nomograms based on tumor stage, PSA value, and Gleason score; 4) delineation of the natural history; 5) revisiting the significance of the androgen/testosterone hypothesis; and 6) devoting special attention to individuals with a certain genetic predisposition. Finally, considering the uncertainty that exists in medicine, risk communication on PSA-based screening is indeed due.


Association Between Preschoolers' Specific Fine (But Not Gross) Motor Skills and Later Academic Competencies: Educational Implications.
Motor development is an inseparable component of cognitive development. So, to develop the mind, it is necessary to work the body. Therefore, Early Childhood Education curricula and the scientific literature emphasize the need to promote the development of motor skills during the 1st years of life. These skills are necessary for learning and subsequent academic performance. However, studies frequently offer only a partial view of these relationships. Few works have analyzed the specific relationships between different components of preschool gross and fine motor skills and subsequent performance on different academic competencies. Further, they present discrepant results. The aim of this study was to determinate which specific components of gross and fine motor skills assessed in Spanish students during the final year of Early Childhood Education (5 to 6-year-olds) were associated with different academic competencies assessed in the following academic year, when the students were in their 1st year of Primary Education. The final sample consisted of 38 Spanish students, aged 5. A mixed methods approach was used. It consisted of systematic observation to assess specific components of gross and fine motor skills when children were in the Early Childhood Education period, and selective methodology to evaluate their academic competencies (specifically in literacy and mathematics and overall), 1 year later, once in Primary Education. Multiple linear regression models were constructed using the computing language R to examine the association between motor skills and academic competencies. The results indicated that only the components of fine motor skills showed associations with academic competencies. The pattern of association varied when literacy and mathematics competencies were specifically and individually assessed and when overall academic competency was considered. The two assessed fine motor skills (Coordination and Integration) were associated with literacy competency (β = 0.344, p = 0.025; β = 0.349, p = 0.024, respectively) and overall academic competency (β = 0.267, p = 0.065; β = 0.493, p = 0.001, respectively). However, only Integration was associated with mathematics competency (β = 0.476, p = 0.002). The "Discussion" section focuses on the educational implications of these results and future research. It highlights the importance of early assessment of fine motor skills to identify students likely to present inadequate subsequent academic performance and the need to apply instruction and interventions tailored to the specific needs of each child.


A case report on the effects of COVID-19 on ANC monitoring in a patient on long-term clozapine treatment.
Clozapine carries a US boxed warning for severe neutropenia, and strict monitoring is required through the FDA's Risk Evaluation and Mitigation Strategy (REMS) program. Patients with confirmed diagnosis of COVID-19 are also at risk for neutropenia. For patients on clozapine, the diagnosis of this novel virus may require an increase in the frequency of scheduled ANC monitoring. A case report of moderate neutropenia following COVID-19 diagnosis that required an increase in the frequency of ANC monitoring in a patient on long-term clozapine treatment is discussed. A 33-year-old white man with schizophrenia had been on clozapine for more than 2 years, with an ANC monitoring schedule once every 4 weeks. The patient was admitted to the hospital for worsening aggressive behavior. On day 11 of hospital admission, he tested positive for COVID-19. Five days following this diagnosis, the patient's ANC dropped from 2.2/L to 0.8/L. This decrease led to daily ANC labs and the clozapine regimen being held for 1 day. Throughout the patient's admission adjustments were made to the frequency of lab monitoring based on fluctuations in his ANC levels. There have been limited case reports on patients receiving clozapine experiencing neutropenia following the diagnosis of COVID-19. To the authors knowledge, this is the first case report from the United States that specifically discusses the required changes to ANC monitoring. Patients on clozapine who test positive for COVID-19 may be at an even greater risk for neutropenia, compared with clozapine patients without COVID-19. Increasing the frequency of ANC monitoring should be considered in the weeks following the diagnosis to ensure that clozapine treatment can be safely adjusted, or even discontinued.


Errors of parameters of distribution functions for spherical bodies stochastically estimated with parallel test lines of regular and narrow intervals.
The parameters of some distribution functions for the radius of spherical bodies randomly dispersed in a three-dimensional space can be estimated with a grating of parallel test lines of regular intervals superposed on a test plane of unit surface area. The interval of the test lines is set narrower than the mean diameter of the circles on the test plane. The errors of number Nlambdao of chords per test line of unit length, arithmetical mean lambda and secondary moment (lambda2) of the length of individual chords are: [C(Nlambdao)*]2=(4/9pi)(Q3/Q2(2))(1/M2lambdaNlambdao)+(4/pi)(lambda/Nlambdao), [C(lambda)*]2=(pi/4)[(32/3pi2) - 1](1/M2lambdaNlambdao)+[(4/pi)-(3pi/8)(Q2(2)/Q3)](lambda/Nlambdao) and [C(lambda2)*]2 = (1024/2025pi)(Q5Q3/Q4(2))(1/M2lambdaNlambdao)+4[(4/pi)-(3pi/8)(Q2(2)/Q3)](lambda/Nlambdao). The first and second terms of the right sides of these expressions represent intraregional and interregional errors, respectively; * denotes the error for the total region; M is the expectation of the number of test lines of unit length covering the test plane; and Qn a quotient (Dn)/Dn of sphere diameter D, n being a positive integer. Intraregional errors are inversely proportional to M2 with the grating, while they are inversely proportional only to M with random test lines. The use of regularly arranged test lines is consequently effective in minimizing intraregional errors.


Understanding the role of serotonin in psychiatric diseases.
Serotonin (5-HT) continues to attract researchers' interest after almost a century. However, despite these efforts, its role has not yet been fully elucidated. It is now evident that 5-HT does not modulate single functions but rather a multiplicity of activities and behaviors present in both normal and several pathological conditions in a less deterministic way than previously assumed. This article aims to briefly review some of the latest advancements in the general role of 5-HT in psychiatry, particularly in depression, and offer the author's personal reflections.


An Unbalanced Weighted Sequential Fusing Multi-Sensor GM-PHD Algorithm.
In this paper, we study the multi-sensor multi-target tracking problem in the formulation of random finite sets. The Gaussian Mixture probability hypothesis density (GM-PHD) method is employed to formulate the sequential fusing multi-sensor GM-PHD (SFMGM-PHD) algorithm. First, the GM-PHD is applied to multiple sensors to get the posterior GM estimations in a parallel way. Second, we propose the SFMGM-PHD algorithm to fuse the multi-sensor GM estimations in a sequential way. Third, the unbalanced weighted fusing and adaptive sequence ordering methods are further proposed for two improved SFMGM-PHD algorithms. At last, we analyze the proposed algorithms in four different multi-sensor multi-target tracking scenes, and the results demonstrate the efficiency.


A Diffusion Model Analysis of Magnitude Comparison in Children with and without Dyscalculia: Care of Response and Ability Are Related to Both Mathematical Achievement and Stimuli.
The respective roles of the approximate number system (ANS) and an access deficit (AD) in developmental dyscalculia (DD) are not well-known. Most studies rely on response times (RTs) or accuracy (error rates) separately. We analyzed the results of two samples of elementary school children in symbolic magnitude comparison (MC) and non-symbolic MC using a diffusion model. This approach uses the joint distribution of both RTs and accuracy in order to synthesize measures closer to ability and response caution or response conservatism. The latter can be understood in the context of the speed-accuracy tradeoff: It expresses how much a subject trades in speed for improved accuracy. We found significant effects of DD on both ability (negative) and response caution (positive) in MC tasks and a negative interaction of DD with symbolic task material on ability. These results support that DD subjects suffer from both an impaired ANS and an AD and in particular support that slower RTs of children with DD are indeed related to impaired processing of numerical information. An interaction effect of symbolic task material and DD (low mathematical ability) on response caution could not be refuted. However, in a sample more representative of the general population we found a negative association of mathematical ability and response caution in symbolic but not in non-symbolic task material. The observed differences in response behavior highlight the importance of accounting for response caution in the analysis of MC tasks. The results as a whole present a good example of the benefits of a diffusion model analysis.


Role of bradykinin potentiation in the antihypertensive effect of captopril in conscious rabbits with two-kidney, one-clip hypertension.
The role of bradykinin potentiation in the antihypertensive effect of captopril was assessed in conscious rabbits with two-kidney, one-clip hypertension. On the 35th day after clipping the renal artery, a bolus injection of bradykinin 0.2 microgram/kg was repeated at 15-min intervals three times before and for 180 min after the administration of captopril 0.5 mg/kg. The magnitude and duration of captopril-induced hypotension were more marked in hypertensive rabbits than in controls. The bradykinin-induced hypotension was markedly enhanced by captopril. However, the bradykinin potentiation by captopril was not correlated with its vasodepressive effect. On the other hand, a close relationship (r = 0.825, p less than 0.001) was observed between plasma renin activity and the maximum reduction in blood pressure induced by captopril. The experiment performed after sodium depletion for 7 days revealed that the bradykinin potentiating effect of captopril was not affected by sodium depletion. Therefore, it is concluded that the vasodepression by captopril does not necessarily depend on its bradykinin potentiating action and the latter is not influenced by the renin-angiotensin system or fluid volume depletion.


AOP Report: Uncoupling of Oxidative Phosphorylation Leading to Growth Inhibition via Decreased Cell Proliferation.
This report describes a novel adverse outcome pathway (AOP) on uncoupling of oxidative phosphorylation (OXPHOS) leading to growth inhibition via decreased adenosine triphosphate (ATP) pool and cell proliferation (AOPWiki, AOP263). Oxidative phosphorylation is a major metabolic process that produces the primary form of energy (ATP) supporting various biological functions. Uncoupling of OXPHOS is a widely recognized mode of action of many chemicals and is known to affect growth via different biological processes. Capturing these events in an AOP can greatly facilitate mechanistic understanding and hazard assessment of OXPHOS uncouplers and growth regulators in eukaryotes. The four proposed key events in this AOP are intentionally generalized to cover a wide range of organisms and stressors. Three out of four events can be measured using in vitro high-throughput bioassays, whereas for most organisms, growth inhibition can also be measured in a high-throughput format using standard in vivo toxicity test protocols. The key events and key event relationships in this AOP are further assessed for weight of evidence using evolved Bradford-Hill considerations. The overall confidence levels range from moderate to high with only a few uncertainties and inconsistencies. The chemical applicability domain of the AOP mainly contains protonophores uncouplers, which can be predicated using the quantitative structure-activity relationship (QSAR) approach and validated using in vitro high-throughput bioassays. The biological domain of the AOP basically covers all eukaryotes. The AOP described in this report is part of a larger AOP network linking uncoupling of OXPHOS to growth inhibition, and is considered highly relevant and applicable to both human health and ecological risk assessments.


HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors.
Vγ9Vδ2 effector T cells lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill defined. We examined lysis mediated by human Vγ9Vδ2 effector T cells in response to the naturally occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. CD27(+)/CD45RA(-) Th1-like effector cells killed K562 target cells through a mechanism that could be enhanced by either compound or TCR Ab and blocked by Src inhibition or butyrophilin 3 isoform A1 (BTN3A1) disruption. Pretreatment at 4 °: C decreased HMBPP-induced lysis but did not reduce lysis induced by bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by Vγ9Vδ2 effector T cells. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by small-molecule induction of BTN3A1.


Late Isometric Assessment of Hip Abductor Muscle and Its Relationship with Functional Tests in Elderly Women Undergoing Replacement of Unilateral Hip Joint.
The aim of this study was to evaluate the recovery of muscle strength and measure autonomy 3 yrs after hip replacement surgery in a sample of patients. Seventy-eight female patients (70.7 ± 6.3 yrs old) operated on for hip replacement were evaluated. They underwent evaluation tests for hip abductor muscle strength on the healthy and operated limb using strength curves obtained with isometric assessments. Autonomy was evaluated with a rating scale Western Ontario and McMaster Universities Arthritis Index (WOMAC), Harris and MOS 36-Item Short-Form Health Survey (SF-36) and functional assessment (Timed 'Up and Go' test). Three years after surgery, a muscle strength deficit was still noticeable on the operated limb compared with the healthy limb ranging from 9% at 5 degrees of adduction to 12% at 0 degree of abduction. The strength curves obtained on the operated side maintained the same descending trend as the healthy side. The authors found no significant correlations between the patient-reported functional measures and the hip abductor strength deficit. The Timed Up and Go test was moderately correlated with the muscle strength deficit. The association between the deficit and the Timed Up and Go test was statistically significant. The evaluation of muscle strength and functional tests are more useful than the rating scales in patients 3 yrs after surgery. The strength curves are useful to have different levels of information and describe joint function.


Scrotal Abdomen: Case Report and Management Principles.
Hernias extending beyond the midpoint of the inner thigh in the standing position are called giant inguinal hernias or scrotal abdomen. They are rarely seen in common surgical practice. Huge inguinal hernias occur after years of neglect by the patient or in areas that are inaccessible to surgical services. Two cases of giant inguinal hernias which were managed successfully are presented here. Case 1: 80-year-old male patient presented with left giant scrotal abdomen for the past 12 years. Preoperatively, the pulmonary function test was found to be normal for his age. He was given incentive spirometry for a week. Perioperatively, the sac contained the entire small bowel, sigmoid colon, and omentum with inter bowel loop adhesions. Adhesions were released and it was repaired by hernioplasty with left orchidectomy. In the postoperative period, the patient was put on non-invasive ventilation for two days and then later was weaned off. Case 2: 42 years male patient presented with right-sided giant inguinoscrotal swelling for the past 15 years. The swelling was extending below midthigh. All the preoperative investigations were normal. Perioperatively, the sac contained omentum and small bowel and it was repaired by right hernioplasty. The postoperative period was uneventful and the patient recovered well. These are interesting cases of giant inguinal hernias. The occurrence of such potentially dangerous surgical problems is more common in low-to-middle income countries owing to the unavailability of surgical services. The management involves specific measures to prepare the patient adequately preoperatively especially to prevent respiratory complications in the postoperative period. Giant inguinal hernias can be comfortably managed if the patients are prepared adequately in the preoperative period. Their postoperative period will be uneventful if their pulmonary functions are normal.


Mechanism of tungsten-dependent acetylene hydratase from quantum chemical calculations.
Acetylene hydratase is a tungsten-dependent enzyme that catalyzes the nonredox hydration of acetylene to acetaldehyde. Density functional theory calculations are used to elucidate the reaction mechanism of this enzyme with a large model of the active site devised on the basis of the native X-ray crystal structure. Based on the calculations, we propose a new mechanism in which the acetylene substrate first displaces the W-coordinated water molecule, and then undergoes a nucleophilic attack by the water molecule assisted by an ionized Asp13 residue at the active site. This is followed by proton transfer from Asp13 to the newly formed vinyl anion intermediate. In the subsequent isomerization, Asp13 shuttles a proton from the hydroxyl group of the vinyl alcohol to the α-carbon. Asp13 is thus a key player in the mechanism, but also W is directly involved in the reaction by binding and activating acetylene and providing electrostatic stabilization to the transition states and intermediates. Several other mechanisms are also considered but the energetic barriers are found to be very high, ruling out these possibilities.


The autoantibody response to Ro/SSA in cutaneous lupus erythematosus.
Seventeen patients with subacute cutaneous lupus erythematosus (SCLE) were compared with 15 patients with discoid lupus erythematosus (DLE) to evaluate the relationship of 60- and 52-kd Ro/SSA autoantibodies to the clinical diagnosis and to evaluate assays for anti-Ro/SSA. All serum samples from patients with SCLE had precipitating anti-Ro/SSA antibodies in immunodiffusion, and all had high titer anti-60-kd Ro/SSA in enzyme-linked immunosorbent assay. Immunoblotting was inadequately sensitive for detecting anti-60-kd Ro/SSA. Fifteen patients with SCLE had anti-52-kd Ro/SSA (11 high titer, four low titer). Only one of the 15 patients with DLE had precipitating, high-titer anti-Ro/SSA. Nine other patients with DLE had low-titer anti-60-kd Ro/SSA, and four had low-titer anti-52-kd Ro-SSA. Low-titer anti-Ro/SSA did not confer an increased risk for photosensitivity in the DLE group. High-titer, precipitating antibodies to Ro/SSA are typical of SCLE and unusual in DLE. Low-titer, nonprecipitating antibodies to Ro/SSA are common in DLE and could be an indication of pathogenic factors shared with SCLE. However, low titers of anti-Ro/SSA do not confer a significant risk for SCLE skin lesions. For the purpose of clinical evaluation of skin disease, immunodiffusion assays for anti-Ro/SSA are cost-effective and informative.


Assessment and Optimizations of Candida albicans In Vitro Biofilm Assays.
Candida albicans biofilms have a significant medical impact due to their rapid growth on implanted medical devices, their resistance to antifungal drugs, and their ability to seed disseminated infections. Biofilm assays performed in vitro allow for rapid, high-throughput screening of gene deletion libraries or antifungal compounds and typically serve as precursors to in vivo studies. Here, we compile and discuss the protocols for several recently published C. albicansin vitro biofilm assays. We also describe improved versions of these protocols as well as novel in vitro assays. Finally, we consider some of the advantages and disadvantages of these different types of assays.


Integrating a tailored e-health self-management application for chronic obstructive pulmonary disease patients into primary care: a pilot study.
Changes in reimbursement have been compelling for Dutch primary care practices to apply a disease management approach for patients with chronic obstructive pulmonary disease (COPD). This approach includes individual patient consultations with a practice nurse, who coaches patients in COPD management. The aim of this study was to gauge the feasibility of adding a web-based patient self-management support application, by assessing patients' self-management, patients' health status, the impact on the organization of care, and the level of application use and appreciation. The study employed a mixed methods design. Six practice nurses recruited COPD patients during a consultation. The e-Health application included a questionnaire that captured information on demographics, self-management related behaviors (smoking cessation, physical activity and medication adherence) and their determinants, and nurse recommendations. The application provided tailored feedback messages to patients and provided the nurse with reports. Data were collected through questionnaires and medical record abstractions at baseline and one year later. Semi-structured interviews with patients and nurses were conducted. Descriptive statistics were calculated for quantitative data and content analysis was used to analyze the qualitative data. Eleven patients, recruited by three nurses, used the application 1 to 7 times (median 4). Most patients thought that the application supported self-management, but their interest diminished after multiple uses. Impact on patients' health could not be determined due to the small sample size. Nurses reported benefits for the organization of care and made suggestions to optimize the use of the reports. Results suggest that it is possible to integrate a web-based COPD self-management application into the current primary care disease management process. The pilot study also revealed opportunities to improve the application and reports, in order to increase technology use and appreciation.


Recent updates on green synthesis of lignin nanoparticle and its potential applications in modern biotechnology.
Lignin is a complex of organic polymers that are abundantly present in the plant cell wall which considered of emerging substrates for various kinds of value-added industrial products. Lignin has potential use for the production of green nanomaterials, which exhibit improved or different properties corresponding to their parent polymers. Nano lignin has received significant interest in recent years due to its applications in numerous fields. Lignin, the abundant and limited functionality has challenges for its potential uses. Creating advanced functional lignin-derived material like lignin nanoparticles (LNPs) which significantly alter the biological process has great potential for its applications. In the fields of biotechnology, several lignin extraction processes from various raw materials and diverse synthesis techniques, including acid precipitation, dialysis, solvent shifting/solvent exchange, antisolvent precipitation, homogenization, water-in-oil (W/O) microemulsion, ultra-sonication, interfacial crosslinking, polymerization, and biological pathway can be employed to produce LNPs. The scientific community has recently become more concerned about the transformation of lignin to lignin nanomaterials, including nanoparticles, nanocapsules, nanofibers, nanotubes, and nanofilms. Recent research has shown that lignin nanoparticles (LNPs) are: non-toxic at adequate amounts (both in vitro and in vivo), are economical, and can be biodegradable by bacteria and fungi. In promising studies, LNPs have been investigated for their potential applications in gene delivery systems, drug carriers, biocatalysts, tissue engineering, heavy metal absorbers, encapsulation of molecules, supercapacitors, hybrid nanocomposites, and other applications. This current review addresses the recent advances in the synthesis of LNPs, their advanced application in different areas, future perspectives, and challenges associated with lignin-based nanomaterials.


Distribution of CORE-OM scores in a general population, clinical cut-off points and comparison with the CIS-R.
Although measures of psychopathology are designed for use in clinical populations, their meaning derives from comparison with normal populations. To compare the distribution of scores on the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) from a general population sample with the distribution in an aggregated clinical sample to derive recommended cut-off points for determining clinical significance. The CORE-OM general population sample was based on a weighted subsample of participants in the psychiatric morbidity follow-up survey who completed valid CORE-OM forms following their interview (effective n=535). Comparison of the CORE-OM general population sample with a clinical sample aggregated from previous studies (n=10761) yielded a cut-off score of 9.9 on the 0-40 scale of the CORE-OM. The CORE-OM was highly correlated (r=0.77) with the Clinical Interview Schedule-Revised, supporting convergent validity. We recommend rounding the CORE-OM cut-off score to 10. However, cut-off scores must be used thoughtfully and adjusted to fit context and purpose.


A case report of a polytrauma patient with penetrating iron rods in thorax and head.
Impalement injury is an uncommon presentation, and penetrating chest injuries account for 1% to 13% of thoracic trauma hospital admissions. The vast majority of patients with penetrating thoracic trauma who survive to reach the hospital alive can be managed nonoperatively. Nevertheless, in 10% to 15% of cases, emergency operation is necessary due to the associated hemorrhagic shock and visceral injury. Here, we report on a 39-year-old male, a construction worker, who fell down from a height of a construction site, landing ventrally on a clump of iron rods with 4 projecting heavy metallic rods penetrating into his thorax and head (scalp pierced only). Emergency surgery was taken, and the patient had an uneventful successful outcome. After massive thoracic impalement, rapid transportation to a tertiary trauma center with the impaled objects in situ can improve the outcome. Video-assisted thoracic surgery (VATS) is recommended to remove the foreign body under direct vision and to reduce the incidence of missed, potentially fatal vascular or visceral injuries.


Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex.
Menin, a gene product of multiple endocrine neoplasia type I (MEN1), is known to act as a tumor suppressor to repress JunD transcription factor. However, the mechanism by which Menin represses JunD transcriptional activity was still unclear. In this study, we found that Menin is a corepressor against JunD transcriptional activity via recruitment of histone deacetylases in an mSin3A-dependent manner. The amino acid search revealed that central domain of Menin includes a alpha-helical mSin3-interacting domain [SID (371-387)]. The SID mutation of Menin (L381P/A385P) abolished the interaction between mSin3A and paired amphipathic helix 2 domain of Menin and reduced its ability to repress JunD transcriptional activity, implicating that SID of Menin is important for recruiting an mSin3A-histone deacetylase complex to repress JunD transcriptional activity.


Critical role of the March of Dimes in the expansion of newborn screening.
Expansion of newborn screening (NBS) has been driven primarily by a combination of advances in technology and medical treatment, and the sustained advocacy efforts of consumers and voluntary health organizations. The longstanding leadership of the March of Dimes has been credited by many as a critical factor in the expansion and improvement of state NBS programs. From the historic vantage point of four decades of March of Dimes involvement with newborn screening, this report reviews the unique origin of the first newborn screening test, and identifies from this point of origin several of the elements which still define the evolution of advocacy for NBS today. It also documents activities at the federal level and in seven states that have lead to expanded screening for newborns. Advances in NBS technology and medical treatment have informed policy development. Mobilization of volunteers and focused advocacy activities have brought about expansion of screening opportunities for newborns across the United States. But more work is needed. Continued application of the effective strategies identified in this report will help assure that all families have the best possible chance of assuring that their newborns do not have to suffer the complications of conditions that we know can be treated effectively.


Regulation of Interferon Induction by the Ubiquitin-Like Modifier FAT10.
The revelation that the human major histocompatibility complex (MHC) class I locus encodes a ubiquitin-like protein designated HLA-F adjacent transcript 10 (FAT10) or ubiquitin D (UBD) has attracted increasing attention to the function of this protein. Interestingly, the pro-inflammatory cytokines interferon (IFN)-γ and tumor necrosis factor (TNF) α synergize to strongly induce FAT10 expression, thereby suggesting a role of FAT10 in the immune response. Recent reports that FAT10 downregulates type I interferon production while it upregulates IFN-γ pose mechanistic questions on how FAT10 differentially regulates interferon induction. Several covalent and non-covalent binding partners of FAT10 involved in signal transduction pathways leading to IFN synthesis have been identified. After introducing FAT10, we review here recent insights into how FAT10 affects proteins in the interferon pathways, like the virus-responsive pattern recognition receptor RIG-I, the ubiquitin ligase ZNF598, and the deubiquitylating enzyme OTUB1. Moreover, we outline the consequences of FAT10 deficiency on interferon synthesis and viral expansion in mice and human cells. We discuss the need for covalent isopeptide linkage of FAT10 to the involved target proteins and the concomitant targeting for proteasomal degradation. After years of investigating the elusive biological functions of this fascinating ubiquitin-like modifier, we review the emerging evidence for a novel role of FAT10 in interferon regulation.


Dominant-negative behavior of mammalian Vps35 in yeast requires a conserved PRLYL motif involved in retromer assembly.
The retromer protein complex assists in recycling selected integral membrane proteins from endosomes to the trans Golgi network. One protein subcomplex (Vps35p, Vps26p and Vps29p) combines with a second (Vps17p and Vps5p) to form a coat involved in sorting and budding of endosomal vesicles. Yeast Vps35p (yVps35) exhibits similarity to human Vps35 (hVps35), especially in a completely conserved PRLYL motif contained within an amino-terminal domain. Companion studies indicate that an R(98)W mutation in yVps35 causes defective retromer assembly in Saccharomyces cerevisiae. Herein, we find that the expression of hVps35 in yeast confers dominant-negative vacuolar proenzyme secretion and defective secretory proprotein processing. The mutant phenotype appears to be driven by hVps35 competing with endogenous yVps35, becoming incorporated into defective retromer complexes and causing proteasomal degradation of endogenous Vps26 and Vps29. Increased expression of yVps35 displaces some hVps35 to a 100 000 x g supernatant and suppresses the dominant-negative phenotype. Remarkably, mutation of the conserved R(107)W of hVps35 displaces some of the protein to the 100 000 x g supernatant, slows protein turnover and restores stability of Vps26p and Vps29p and completely abrogates dominant-negative trafficking behavior. We show that hVps35 coprecipitates Vps26, whereas the R(107)W mutant does not. In pancreatic beta cells, the R(107)W mutant shifts hVps35 from peripheral endosomes to a juxtanuclear compartment, affecting both mannose phosphate receptors and insulin. These data underscore importance of the Vps35 PRLYL motif in retromer subcomplex interactions and function.


Computer-assisted prosthetic planning and implant design with integrated digital bite registration: a treatment protocol.
The aim of this clinical study is to present an integrated digital project through the description of a clinical case, made entirely in digitized form, taking advantage of the opportunity offered by instrumental diagnostic software. A case report participant is a 65-year-old female patient presents with loss of diffuse bone support, caused by periodontal disease. After a sign of an informed consent and an explication of a plan of treatment, technical intraoral and extraoral pictures and intraoral digital impressions were taken. The digital images improved from the 2D Smile Lynx Software and the scanner stereolithographic (STL) file was matched into the CAD Lynx to obtain a virtual previsualization of teeth and smile design, and to mill the provisional and the definitive crowns. The digital prosthetic design allows the evaluation of the dental parameters in relation to the parameters of the patient's face for the new prosthetic project and the radiological examination using CBCT guides the insertion of the fixtures for the rehabilitation phase. The surgical and prosthetic design are subsequently integrated. The evaluation of the bone bases is carried out with a radiological diagnostic software for CT (Real Guide 5.0-3Diemme, Cantù-Italy) which can virtually design the implant insertion. The functional examination of the patient is carried out through an occlusion-postural examination that uses digital electromyographic assessments. The integrated digital protocol proposal inserts in the rehabilitation path the digital recording of the free mandibular movement, as well as the scan of the patient's face, data that will be integrated into the CAD software for the design of temporary and definitive prosthetic artifacts, made using the CAM method. This study showed guided implant placement and the application of fixed implant-supported prosthetic restorations carried out with a fully digital workflow, dependent on the functional digital evaluation of the patient's occlusion. The proposed protocol described the correct use of digitalization of clinical, surgical, and prosthetic procedures, and the matching of the data into a computerized environment, to improve team communication and to take advantage of the combination of collected data to not lose information using classic manual steps.


[Role of a local therapeutic service in the timely identification, treatment, and rehabilitation of patients with coronary heart disease].
Local polyclinic therapists' long experience in timely identifying, treating and rehabilitating patients with coronary heart disease (CHD) is analyzed. A local therapist's attention is given to diferent course types--the clinical manifestations of CHD. The principles of continuity in the work of a therapist and a hospital: possibilities of extrahospital treatment are denoted; indications for hospitalization are specified. Rehabilitative measures include psychotherapy sessions in addition to drug, dietary, and exercise therapies. Continuity in the work of a therapeutic unit and a sociomedical expert commission contributes to the elaboration of clearer criteria for determining the degree of working capacity loss.


Substantia nigra stimulation influences monkey superior colliculus neuronal activity bilaterally.
The inhibitory drive arising from the basal ganglia is thought to prevent the occurrence of orienting movements of the eyes, head, and body in monkeys and other mammals. The direct projection from the substantia nigra pars reticulata (SNr) to the superior colliculus (SC) mediates the inhibition. Since the original experiments in the SNr of monkeys the buildup or prelude neuron has been a focus of SC research. However, whether the SNr influences buildup neurons in SC is unknown. Furthermore, a contralateral SNr-SC pathway is evident in many species but remains unexplored in the alert monkey. Here we introduced electrical stimulation of one or both SNr nuclei while recording from SC buildup neurons. Stimulation of the SNr reduced the discharge rate of SC buildup neurons bilaterally. This result is consistent with activation of an inhibitory drive from SNr to SC. The time course of the influence of ipsilateral SNr on the activity of most SC neurons was longer (approximately 73 ms) than the influence of the contralateral SNr (approximately 34 ms). We also found that the variability of saccade onset time and saccade direction was altered with electrical stimulation of the SNr. Taken together our results show that electrical stimulation activates the inhibitory output of the SNr that in turn, reduces the activity of SC buildup neurons in both hemispheres. However, rather than acting as a gate for saccade initiation, the results suggest that the influence of SNr inhibition on visually guided saccades is more subtle, shaping the balance of excitation and inhibition across the SC.


Fluid Imbalance in Geriatrics: The Need for Optimal Hydration.
In the elderly, increased morbidity and mortality are often linked to fluid and electrolyte imbalances due to age-related physiological changes, hence monitoring and maintaining healthy hydration levels is important for the geriatric patient population. Patients recuperating from an illness at home maybe likely to neglect proper fluid intake and energy management, which hampers their timely recovery. In elderly patients with concurrent illnesses and therapies, dehydration is a common condition that often remains unnoticed despite persistent disease symptoms. Oral nutritional supplements such as scientifically formulated oral rehydration therapies (ORTs) have been recommended in such cases. These supplements can be further suggested by nutritional counseling, diet modification, nursing interventions, and educating the patients. The main aim of this review is to generate a greater understanding of the fluid intake requirements for the elderly, thus contributing to the prevention of the negative effects of dehydration. This review comprehensively highlights the need for treatment, recovery from illness to supportive care to address a patient's needs. Maintaining an optimal hydration level aids the efficacy of therapy in elderly patients. Hospitalized patients are considered to be at risk of dehydration, whereas patients at home completely ignore the need for fluid and energy management, leading to hospital readmissions and delayed recovery. Guidelines are available for treating, managing, and maintaining ideal hydration levels, these are considered to be imperative in managing elderly patients with chronic illnesses.


An alternative interpretation of the slow KaiB-KaiC binding of the cyanobacterial clock proteins.
The biological clock of cyanobacteria is composed of three proteins, KaiA, KaiB, and KaiC. The KaiB-KaiC binding brings the slowness into the system, which is essential for the long period of the circadian rhythm. However, there is no consensus as to the origin of the slowness due to the pre-binding conformational transition of either KaiB or KaiC. In this study, we propose a simple KaiB-KaiC binding scheme in a hexameric form with an attractive interaction between adjacent bound KaiB monomers, which is independent of KaiB's conformational change. We then show that the present scheme can explain several important experimental results on the binding, including that used as evidence for the slow conformational transition of KaiB. The present result thus indicates that the slowness arises from KaiC rather than KaiB.


An UPLC-MSMS method to measure plasma homocysteine concentration.
Homocysteine (Hcy) is monitored in a growing number of diseases and requires a rapid and reliable method to measure its concentration in routine practice. We validated a new mass spectrometry method to measure plasma Hcy concentration and to determinate our own targeted concentrations according to COFRAC (French accreditation committee) recommendations. We collected the Hcy concentrations measured in the laboratory from 2014 to 2015 and we compared the values between different clinical groups. We obtained excellent performances of reproducibility, sensitivity (coefficient of variation <10%). We determined new ranges of normal values 12.4 [11.8-13.0] μmol/L. This new method is thus rapid, robust and suitable for its use in routine practice to respond to the increase of prescriptions.


Characterization of Leuconostoc carnosum and Latilactobacillus sakei during Cooked Pork Ham Processing.
Cooked ham is a popular, ready-to-eat product made of pork meat that is susceptible to microbial growth throughout its shelf life. In this study, we aimed to monitor the microbial growth and composition of nine vacuum-packed cooked ham lots using plate counting until the microbial limit of 7.4 log10 AMC/LAB CFU/g was exceeded. Eight out of nine lots exceeded the microbial limit after 20 days of storage. Lactic acid bacteria strains, particularly Leuconostoc carnosum and Latilactobacillus sakei, prevailed in vacuum-packed cooked ham. Leuconostoc carnosum 2 (Leuc 2) and Latilactobacillus sakei 4 (Sakei 4) were isolated from raw meat and the post-cooking area of the food processing facility. Carbohydrate utilization patterns of Leuc. carnosum PFGE types isolated from raw meat and the food processing environment differed from those isolated from cooked ham. These findings demonstrate how raw meat and its processing environment impact the quality and shelf life of cooked ham.


Tumor markers in familial Mediterranean fever and their correlation with the frequency of attacks.
Serum levels of tumor markers can be elevated in several benign diseases affecting the serosal surfaces. Familial Mediterranean fever (FMF) is a genetic disease characterized by acute attacks of fever and inflammation of the serosal membranes. The aim of this study was to examine the levels of tumor markers in FMF patients and their correlation with the frequency of attacks. Serum levels of CA 125, CA 19-9, CA 15-3, CA 72-4, CEA, and AFP were measured by ELISA in 36 patients with a definitive diagnosis of FMF (21 males, 15 females, mean age 36.4+/-10.3 yrs) and in 19 healthy controls. Serum levels of all tumor markers were normal in the controls. In FMF patients serum levels of CA 125, CA 19.9, CA 15.3, CEA and AFP were within normal ranges, whereas CA 72.4 was significantly higher than in the controls (p=0.001). Half of the FMF patients showed increased levels of CA 72.4; the mean level was lower in those in complete remission. However, no statistically significant correlation was found between FMF attacks and acute phase reactant levels. With the exception of Ca 72.4, serum levels of tumor markers are not affected by changes in inflammatory cytokines levels during FMF attacks.


Arrest of Langmuir wave collapse by quantum effects.
The arrest of Langmuir wave collapse by quantum effects, first addressed by Haas and Shukla [Phys. Rev. E 79, 066402 (2009)] using a Rayleigh-Ritz trial function method is revisited, using rigorous estimates and systematic asymptotic expansions. The absence of blow up for the so-called quantum Zakharov equations is proved in two and three dimensions, whatever the strength of the quantum effects. The time-periodic behavior of the solution for initial conditions slightly in excess of the singularity threshold for the classical problem is established for various settings in two space dimensions. The difficulty of developing a consistent perturbative approach in three dimensions is also discussed and a semiphenomenological model is suggested for this case.


Evaluation of an algorithm based on peripheral blood hematopoietic progenitor cell and CD34+ cell concentrations to optimize peripheral blood progenitor cell collection by apheresis.
Quantification of peripheral blood (PB) CD34+ cells is commonly used to plan peripheral blood progenitor cell (PBPC) collection but is time-consuming. Sysmex has developed a hematology analyzer that can quickly identify a population of immature hematopoietic cells (HPCs) according to cell size, cell density, and differential lysis resistance, which may indicate the presence of PBPCs in PB. This prospective study has evaluated the potential of such method to predict the PBPC mobilization. A total of 141 patients underwent PBPC mobilization. PB HPCs and PB CD34+ cells were simultaneously quantified with a hematology analyzer (SE2100, Sysmex) and flow cytometry, respectively. The number of blood volumes processed was then based on PB CD34+ cell concentration. The optimal PB HPC level able to predict a minimal level of 10 x 10(6) PB CD34+ cells per L was 5 x 10(6) per L with positive and negative predictive values of 0.93 and 0.36 percent, respectively. For this cutoff point, sensitivity and specificity were 0.81 and 0.65, respectively. The median number of blood volumes processed according to the PB CD34+ cell count allowed us to perform only one apheresis procedure for a majority of patients. PB HPC quantification is very useful to quickly determine the initiation of PBPC apheresis especially for patients with higher concentrations. For patients exhibiting a lower HPC count (<5 x 10(6)/L), other parameters such as a CD34 test may be needed. Such a policy associated with a length of apheresis adapted to the richness in the PB CD34+ cells allows for optimizing the organization of centers with an improvement in patient comfort and economical savings.


Environmental temperature and case fatality of patients with Ebola virus disease in Sierra Leone and Liberia, 2014-2015: a retrospective cohort study.
Fluid loss during Ebola virus disease (EVD) infections from gastrointestinal dysfunction leads to volume depletion. It is possible that high environmental temperatures may exacerbate volume depletion or interfere with the provision of medical care by providers in full personal protective equipment. We investigated the effect of environmental temperature on case fatality. The International Medical Corps (IMC) operated five Ebola Treatment Units (ETUs) in Liberia and Sierra Leone during the 2014-2016 epidemic. Demographic and outcomes variables for 465 patients with EVD were sourced from a de-identified, quality-checked clinical database collected by IMC. Daily environmental temperature data for Liberia and Sierra Leone were collected from a publicly available database (Weather Underground). Mean daily environmental temperatures were averaged across each patient's ETU stay and environmental temperature thresholds were determined. Multiple logistic regression was utilised, with forward variable selection and threshold for entry of P < 0.1. Statistical significance was defined as P < 0.05. The following variables were analysed as potential confounders: age, sex, ETU, length of ETU operation and date of treatment. Case fatality was 57.6% among patients diagnosed with EVD. Analysis of case fatality across environmental temperature quintiles indicated a threshold effect; the optimal threshold for average environmental temperature during a patient's ETU stay was determined empirically to be 27.4 °C (81.3 °F). Case fatality was significantly greater for patients with average environmental temperatures above the threshold (70.4%) vs. below (52.0%) (P < 0.001). In multiple regression, patients with average environmental temperature above the threshold during their ETU stay were significantly more likely to die than patients below the threshold (aOR = 2.5, 95% CI 1.6-3.8, P < 0.001). This trend was observed only among patients treated in white tent ETUs, and not in ETUs with aluminium roofs. These findings suggest that an average environmental temperature above 27.4 °C (81.3 °F) during patients' ETU stay is associated with greater risk of death among patients with EVD. Further studies should investigate this effect. These results have potential implications for reducing case fatality through improved ETU construction or other temperature control methods within ETUs during future outbreaks.