Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study.
The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (β=-0.399, p=0.040) and deep (β=-0.556, p=0.010) GM volume, lower mean cortical thickness (β=-0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.


Effects of vesicoureteric reflux on renal growth and function as measured by GFR, plasma creatinine and urinary concentrating ability. An experimental study in the minipig.
The influence of vesicoureteric reflux (VUR) on renal growth and function measured by glomerular filtration rate (GFR), plasma creatinine concentration and urinary concentrating ability has been examined in a simple one-kidney model in the growing minipig over a period of approximately 5 months. Animals with reflux in association with low voiding pressures and normal bladder function (n = 6), as well as those with raised voiding pressures and abnormal bladder function (n = 5), were investigated together with appropriate non-refluxing controls (n = 12). Urinary infection and renal scarring were avoided since these factors may affect kidney function and growth independently. Statistical tests of difference failed to demonstrate any effect of VUR on 51Cr EDTA GFR or renal growth even in the presence of elevated voiding pressures and abnormal detrusor function. However, a significant association between VUR and reduced urinary concentrating ability was shown.


Dyslipidemia and Rate of Under-Target Low-Density Lipoprotein-Cholesterol in Patients with Coronary Artery Disease in Korea.
The aim of this study was to evaluate under target rates of low-density lipoprotein-cholesterol (LDL-C) in Korean patients with stable coronary artery disease (CAD) or an acute coronary syndrome (ACS) in real world practice. Dyslipidemia International Study II was an international observational study of patients with stable CAD or an ACS. Lipid profiles and use of lipid-lowering therapy (LLT) were documented at enrollment, and for the ACS cohort, 4 months follow-up was recommended. Rates of under target LDL-C as per European guidelines, were evaluated, and multivariate regression was performed to identify predictive factors of patients presenting under the target. A total of 808 patients were enrolled in Korea, 500 with stable CAD and 308 with ACS. Of these, 90.6% and 52.6% were being treated with LLT, respectively. In the stable CAD group, 40.0% were under target LDL-C, while in ACS group, the rate was 23.7%. A higher statin dose was independently associated with under target LDL-C in both groups (OR, 1.03; p=0.046 [stable CAD] and OR, 1.05; p=0.01 [ACS]). The mean statin dosage (atorvastatin equivalent) was 17 mg/day. In the 79 ACS patients who underwent the follow-up examination, the LDL-C under target rate rose to 59.5%. Only a minority of patients with stable CAD or ACS were under their target LDL-C level at enrollment. The statin dose was not sufficient in the majority of patients. These results indicate a considerable LLT gap in Korean patients with established CAD.


Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence.
Monoamine oxidase (MAO) isoenzymes A and B are mitochondrial-bound proteins, catalyzing the oxidative deamination of monoamine neurotransmitters as well as xenobiotic amines. Although they derive from a common ancestral progenitor gene, are located at X-chromosome and display 70% structural identity, their substrate preference, regional distribution, and physiological role are divergent. In fact, while MAO-A has high affinity for serotonin and norepinephrine, MAO-B primarily serves the catabolism of 2-phenylethylamine (PEA) and contributes to the degradation of other trace amines and dopamine. Convergent lines of preclinical and clinical evidence indicate that variations in MAO enzymatic activity--due to either genetic or environmental factors--can exert a profound influence on behavioral regulation and play a role in the pathophysiology of a large spectrum of mental and neurodegenerative disorders, ranging from antisocial personality disorder to Parkinson's disease. Over the past few years, numerous advances have been made in our understanding of the phenotypical variations associated with genetic polymorphisms and mutations of the genes encoding for both isoenzymes. In particular, novel findings on the phenotypes of MAO-deficient mice are highlighting novel potential implications of both isoenzymes in a broad spectrum of mental disorders, ranging from autism and anxiety to impulse-control disorders and ADHD. These studies will lay the foundation for future research on the neurobiological and neurochemical bases of these pathological conditions, as well as the role of gene × environment interactions in the vulnerability to several mental disorders.


Potency of several non-steroidal antiinflammatory drugs on airways responses to histamine.
The effects of four non-steroidal antiinflammatory drugs (NSAIDs, indomethacin, flufenamate, aspirin and phenylbutazone) were investigated in anesthetized guinea-pigs. Bronchoconstriction (increased airways resistance and decreased conductance and compliance) was obtained to histamine (1-3 micrograms/kg i.v.). Each of the NSAIDs (0.1-20 mg/kg i.v.) enhanced bronchoconstriction to histamine. Maximum effects were obtained 12-44 min after administration of the NSAID. The order of potency of the drugs in causing a 50% increase in resistance responses to histamine was indomethacin greater than flufenamate greater than aspirin greater than phenylbutazone.


National Minimum Data Set for Antimicrobial Resistance Management: Toward Global Surveillance System.
Success of infection treatment depends on the availability of accurate, reliable, and comprehensive data, information, and knowledge at the point of therapeutic decision-making. The identification of a national minimum data set will support the development and implementation of an effective surveillance system. The goal of this study was to develop a national antimicrobial resistance surveillance minimum data set. In this cross-sectional and descriptive study, data were collected from selected pioneering countries and organizations which have national or international antimicrobial resistance surveillance systems. A minimum data set checklist was extracted and validated. The ultimate data elements of the minimum data set were determined by applying the Delphi technique. Through the Delphi technique, we obtained 80 data elements in 8 axes. The resistance data categories comprised basic, clinical, electronic reporting, infection control, microbiology, pharmacy, World Health Organization-derived, and expert-recommended data. Relevance coding was extracted based on the Iranian electronic health record coding system. This study provides a set of data elements and a schematic framework for the implementation of an antimicrobial resistance surveillance system. A uniform minimum data set was created based on key informants' opinions to cover essential needs in the early implementation of a global antimicrobial resistance surveillance system in Iran.


Neuropsychological functioning and jumping to conclusions in recent onset psychosis patients.
The reasoning bias of jumping to conclusions (JTC) consists of a tendency to make assumptions having little information. The aim of this study was to estimate the differences in neuropsychological functioning between recent onset psychotic patients who jump to conclusions and those who do not jump to conclusions. One hundred and twenty-two patients with a recent onset of a psychotic disorder were assessed with three JTC tasks and a neuropsychological battery exploring verbal learning, memory, attention, psychomotor speed, visuoperceptual abilities, working memory, problem solving, executive functioning. A total of 29.7% (n=36) of the individuals jumped to conclusions in Task 1, 14.0% (n=17) in Task 2, and 15.7% (n=19) in Task 3. People who jump to conclusions in three tasks scored significantly worse in many neuropsychological domain deficits, including attention (p<0.001-0.020), psychomotor speed (p<0.001), working memory (p<0.001-0.040), and executive functioning (p<0.001-0.042). The present study demonstrates that JTC is present even in early stages of the illness, and that there is a relationship between JTC and neuropsychological functioning.


Application and modification of the circular skin excision and pursestring procedures.
The concept of the circular excision is not new. However, it was complicated by excessive postoperative areolar stretching and scar hypertrophy. The Benelli principle of a permanent subdermal pursestring suture overcame these drawbacks. We present our experiences with the circular skin excision for mastopexy procedures and for circular skin incision for total mastectomy and immediate reconstruction.


Wastewater disinfection by ozone: main parameters for process design.
Wastewater disinfection by ozone was investigated at pilot scale on different wastewater effluents. Variations in operating conditions showed that a very low hydraulic retention time (2 min) was sufficient for efficient fecal coliform inactivation, provided a sufficient ozone dose was transferred to the effluent. Therefore, the transferred ozone dose appeared to be the critical parameter for the design of wastewater disinfection. As a consequence, the "Ct" approach commonly applied in drinking water treatment should not be used for wastewater ozonation. Design parameters of ozonation were proposed for two types of regulations, and for effluents of different qualities. It was demonstrated that only with an efficient filtration step one can meet stringent standards such as the California Title 22 criteria. In all cases, viruses were totally inactivated; consequently, viruses do not constitute a limiting factor in wastewater disinfection by ozone. The standard drinking water model failed to match the experimental data obtained on real wastewater effluents. A modified approach was successfully developed, based on the simultaneous consumption of ozone by the microorganisms and the organic matrix.


NRP1 contributes to stemness and potentiates radioresistance via WTAP-mediated m6A methylation of Bcl-2 mRNA in breast cancer.
NRP1 is a transmembrane glycoprotein that is highly expressed in a variety of tumors. There is evidence that NRP1 can enhance the stem cell properties of tumor cells, which are thought to be resistant to radiotherapy. This study aims to elucidate the potential mechanism of NRP1 in radiation resistance. We transfected NRP1 siRNA and plasmid in breast cancer cells to detect the expression of cancer stem cell markers by western blot and qRT-PCR. The effect of NRP1 on radiotherapy resistance was assesses by immunofluorescence and flow cytometry. In vivo, we established xenograft tumor model treating with shRNA-NRP1 to assess radiotherapy sensitivity. We found that NRP1 could enhance the stem cell properties and confer radioresistance of breast cancer cells. Mechanistically, we proved that NRP1 reduced IR-induced apoptosis by downregulation of Bcl-2 via methyltransferase WTAP in m6A-depentent way. It is suggested that these molecules may be the therapeutic targets for improving the efficacy of radiotherapy for breast cancer.


Reactivation of Parvovirus B19 Infection: An Uncommon Trigger of Macrophage Activation Syndrome in Adult-Onset Still's Disease.
A 40-year-old woman presented with four weeks of intermittent high-grade fever, cough, and joint pain, and two weeks of a generalized rash. She was found to have adult-onset Still's disease (AOSD) and rapidly developed macrophage activation syndrome (MAS) on the second day of admission. Among infectious etiologies, Epstein-Barr virus and members of the herpes virus family are common triggers of MAS. However, our patient was found to have reactivation/recurrence of parvovirus B19 infection as the cause; this is an uncommon trigger reported infrequently in the medical literature. Despite intensive treatment, the patient passed away.


Precision of suture placement with microscope- and loupe-assisted anastomoses.
Twenty-eight anastomoses involving seven surgeons were done on 2 mm Gortex vascular prostheses to test the effect of magnification on the precision of suture placement. One-half were done with 3.5-4x prism loupe magnification and the other one-half with 8-30x microscope magnification. The variability of suture placement (defined here as precision) was measured in a blinded fashion. The mean suture puncture to prosthesis edge measurement for the microscope-assisted group was approximately 0.03 mm closer to the edge. The variability from the mean for the microscope-assisted group was approximately 0.01 mm less than that for the loupe-assisted group. This difference was statistically significant at a P value of 0.0123.


Association of Single Nucleotide Polymorphism -2548 G/A (rs12112075) of leptin gene with endometrial cancer and uterine leiomyomas.
The aim of this study was to analyse the frequencies of genotypes and alleles of Single Nucleotide Polymorphism (SNP) -2548 G/A (rs12112075) of leptin gene (LEP) and an attempt to evaluate the effect this DNA marker has on endometrial cancer (EC) and uterine leiomyomas (UL). The study comprised 120 patients treated for endometrial cancer and 90 patients treated for uterine leiomyomas. 90 disease-free individuals were used as controls. In total, 300 patients were investigated in this research. In this paper we have demonstrated that genotype AG of SNP -2548 G/A of LEP may reduce the risk of developing endometrial cancer, whereas allele A itself may be a risk factor of this malignancy. No association was found between the studied polymorphism and uterine leiomyomas. -2548 G/A SNP of LEP may play a significant role in the development of EC, however, uterine leiomyomas are not associated with this DNA marker.


Characteristics of Sleep-Wakefulness Cycle and Circadian Activity in the Lesser Mouse-Deer (Tragulus kanchil).
The pattern of sleep and circadian activity of the lesser mouse-deer (Tragulus kanchil) that is the smallest (body mass between 1.5 and 2.2 kg) representative of the basal group (Tragulidae) of even-toed ungulates which evolved 40-50 Ma were studied. In naturalistic conditions, a total of 30 days of full-day video of the animal behavior and 15 days of 24-h polysomnographic data were collected in 6 animals. The mouse-deer were active less than 20% of 24 h and were quiescent during 60-80% of the remaining time. Slow wave sleep (SWS) accounted for on average 49.7 ± 3.7% of 24 h and paradoxical (rapid eye movement, REM) sleep accounted for 1.7 ± 0.3% of 24 h. During the majority of SWS (87.0 ± 4.4%) the eyes were open. The most of SWS and REM sleep occurred during the daytime hours (9 a.m. to 4 p.m.) and in the first half of the night (8 p.m. to 2 a.m.); the animals were most active during twilight hours (4-6 a.m. and 6-7 p.m.). We suggest that the main features of sleep in the mouse-deer are largely determined by ecological factors, including environmental temperature and predation, as well as the size and physiology of the mouse-deer.


Ammonia exposure and hazard assessment for selected household cleaning product uses.
There is scant information pertaining to airborne ammonia exposures from either spills or common household uses of ammonia-containing floor and tile cleaners or from spray-on glass cleaners. We assessed instantaneous and event-specific time-weighted average (TWA) exposures to airborne ammonia during spills and use (per label directions) of a household floor and tile cleaner and two spray-on window cleaners. Airborne ammonia levels measured at breathing zone height (BZH) above the spilled floor and tile cleaner product reached 500 p.p.m. within 5 min, while levels for spilled window cleaner were below 8 p.p.m. TWA exposures were assessed while tile walls and floors were cleaned in three different bathrooms of a residence, and during use of a spray-on glass cleaner while washing several large windows in an office setting. NIOSH Method 6015 was utilized with concurrent field measurements every 60 s using a Drager PAC III monitor with an electrochemical cell detector. Peak ammonia levels ranged from 16 to 28 p.p.m. and short-term TWA concentrations ranged from 9.4 to 13 p.p.m. during mixing (0.1% ammonia) and cleaning tiles in the three bathrooms. Ammonia exposures while using spray-on window cleaner were over 10-fold lower (TWA=0.65 p.p.m.). Use of the floor and tile cleaner mixed at 0.2% ammonia led to peak airborne ammonia levels within 3-5 min at 36-90 p.p.m., and use of full strength cleaner (3% ammonia) led to peak ammonia levels of 125 to >200 p.p.m. within 2-3 min. Spillage or intentional use of the full strength floor and tile cleaner led to airborne ammonia concentrations that exceed occupational short-term exposure limits, while spillage or use of the spray-on window cleaner did not approach potentially hazardous airborne ammonia levels and likely represents a minimal inhalation health hazard. We conclude that routine household uses of ammonia are unlikely to produce significant exposures when using standard cleaning solutions (0.1-0.2%), but spillage or use of concentrated ammonia solutions (e.g., 3%) in poorly ventilated areas can lead to potentially hazardous airborne ammonia exposures.


Characterization of nuclear localization signal in the N terminus of integrin-linked kinase-associated phosphatase (ILKAP) and its essential role in the down-regulation of RSK2 protein signaling.
Integrin-linked kinase-associated phosphatase (ILKAP) is a serine/threonine (S/T) phosphatase that belongs to the protein phosphatase 2C (PP2C) family. Many previous studies have demonstrated that ILKAP plays key roles in the regulation of cell survival and apoptosis. Researchers have thus far considered ILKAP a cytoplasmic protein that negatively regulates integrin signaling by interacting with and phosphorylating integrin-linked kinase 1 (ILK1). In this study, we found that both endogenous and tagged ILKAP mainly localize to the nucleus and that the nuclear transport of ILKAP is nuclear localization signal (NLS) importin-mediated. The ILKAP protein interacts directly with importin α1, α3, and α5. The NLS in ILKAP is located in the N-terminal region between amino acids 71 and 86, and the NLS-deleted ILKAP protein was distributed in the cytoplasm. In addition, we show that Lys-78 and Arg-79 are critical for the binding of ILKAP to importin α. We also found that nuclear ILKAP interacts with ribosomal protein S6 kinase-2 (RSK2) and induces apoptosis by inhibiting RSK2 activity and down-regulating the expression level of the RSK2 downstream substrate cyclin D1. These results indicate that ILKAP is a nuclear protein that regulates cell survival and apoptosis through the regulation of RSK2 signaling.


Lacidipine: a dihydropyridine calcium antagonist with antioxidant activity.
Lacidipine, a new, long-acting antihypertensive dihydropyridine calcium antagonist was tested for potential antioxidant effect in a series of tests that consider specific radical species. A direct quenching of several radical species could be measured. Moreover, in biological membranes deriving from rat brain tissue, lacidipine showed an activity comparable to reference antioxidant compounds like vitamin E.


Survivor guilt after downsizing.
Like it or not, workforce reduction has become a strategy to achieve or maintain financial solvency. As nurse leader, how can you move staff forward amidst restructuring?


Herpes zoster ophthalmicus followed by contralateral hemiparesis: report of two cases and review of literature.
Two patients with herpes zoster ophthalmicus and contralateral hemiparesis are described, and their findings compared with 49 patients previously reported. These patients presented with delayed contralateral hemiparesis approximately seven weeks after the onset of herpes zoster ophthalmicus. Most patients had evidence of infarction of the ipsilateral middle cerebral artery by angiography or by CT scan. Cerebrospinal fluid pleocytosis and elevated protein commonly were found. Twenty per cent of the reported patients died, but they were older than the patients who survived and predisposed to have diffuse CNS lesions. The pathogenesis of this syndrome is thought to be due to direct viral invasion of the blood vessel wall with resulting angiitis. Further studies need to be performed to clarify the role of specific antiviral therapy or anti-inflammatory agents in treating this complication of herpes zoster.


Polypoid lesion of the stomach: resection through the fiberoptic endoscope.
Endoscopic removal of gastric polyps was done in six patients. Because most gastric polyps are benign and the malignant neoplasm is limited to the polyp without distant metastasis, local excision should be the treatment of choice.


Analysis of Cyclooxygenase 2, Programmed Cell Death Ligand 1, and Arginase 1 Expression in Human Pituitary Adenoma.
Cyclooxygenase 2 (COX-2) is a key enzyme in the synthesis of prostaglandins. Recent studies have shown that overexpression of COX-2 can reduce the antitumor effect of the immune system by inhibiting the proliferation of B and T lymphocytes. Programmed cell death ligand 1 (PD-L1) was the first functionally characterized ligand of programmed cell death protein 1. It plays an important role in maintaining peripheral and central immune tolerance by combining with programmed cell death protein 1. Arginase 1 (ARG1) can process L-arginine in the local microenvironment and affect the function of T cells, resulting in immune escape. In this study, COX-2, PD-L1, and ARG1 expression in human pituitary adenoma (PA) and their relationship were investigated, which provided an initial theoretic basis for further study of the immune escape mechanism in PA in cellular and animal experiments. The protein expression of COX-2, PD-L1, and ARG1 in 55 PA samples was detected by immunohistochemistry, with 10 normal brain tissues as the control group. The location of COX-2, PD-L1, and ARG1 in PA cells was studied by double immunofluorescence colocalization. The results of immunohistochemistry were further verified by Western blot. The expression of COX-2, PD-L1, and ARG1 in PA was significantly higher than that in normal brain tissue. In functional PA (FPA) and nonfunctional PA (NFPA), there was no significant difference in the expression of COX-2 and PD-L1, whereas ARG1 was higher in NFPA. Moreover, the protein expression level of COX-2 was positively correlated with that of PD-L1 and ARG1, and the expression of PD-L1 was positively correlated with that of ARG1. Immunofluorescence confocal imaging showed that COX-2, PD-L1, and ARG1 were all expressed in the cytoplasm of PA cells, and the physical positions of COX-2, PD-L1, and ARG1 were partially coincident. These findings indicate that overexpression of COX-2, PD-L1, and ARG1 may be involved in the pathogenesis of PA. ARG1 plays a more important role in the development of NFPA. By upregulating the expression of PD-L1, COX-2 may promote the expression of ARG1, forming the COX-2/PD-L1/ARG1 signal pathway in promoting the occurrence and development of PA. Perhaps further study of the pathogenesis of PA can start with the mechanism of immune escape.


Patterns and trends in cancer mortality in Colombia 1984-2008.
Cancer has become increasingly acknowledged as a public health issue in Colombia. Rates of the most common malignancies have been generally increasing. We update an evaluation of mortality trends in the major cancers in Colombia one decade ago, discussing the trends in the context of cancer control. We calculated the annual age-standardized mortality rates for the major cancer sites by sex between 1984 and 2008; we also present the estimated annual percentage change (EAPC) for the entire period and for the last decade. There was an average of 32,000 cancer deaths annually in Colombia in the period studied. Overall cancer mortality rates decreased slightly in both men and women. The four most common sites of cancer death among men were stomach (17.6%), prostate (15.0%), lung (14.8%) and colorectum (6.5%). In women, the most common cancer sites were breast (12.3%), cervix (12.1%), stomach (11.5%) and lung (9.2%). Colorectal and CNS cancers exhibited the greatest increases (EAPC of 2.0% and 3.4% respectively) while the largest declines were seen for cancers of the larynx, stomach and oesophagus (EAPC between -3% and -4%). In the last decade, the greatest declines were seen in cervical cancer mortality rates (EAPC = -3.2). The slight decrease in mortality trends from all cancers combined is partially driven by the strong declines in mortality of stomach and cervical cancer. It may be still too early to properly evaluate trends in mortality due to other cancers and the relative impact of changing access to health care in Colombia.


Conformational study of the electronic interactions and nitric oxide release potential of new S‑nitrosothiols esters derivatives of ibuprofen, naproxen and phenyl acids substituted (SNO-ESTERS): Synthesis, infrared spectroscopy analysis and theoretical calculations.
The conformational study on the new S‑nitrosothiols esters (SNO-ESTERS): para-substituted (X = H, OMe, Cl and NO2) S‑nitrosothiol derivatives 2‑methyl‑2‑(sulfanyl)propyl phenylacetates (R1), 2‑(4‑isobutylphenyl)propanoate (ibuprofen, R2), and 2‑(4‑isobutylphenyl)propanoate of 2‑methyl‑2‑(nitrososulfanyl)propyl (naproxen, R3) was performed using infrared spectroscopy (IR) in solvents with increasing polarity (CCl4, CH3Cl, and CH3CN), and theoretical calculations, to determine the preferential conformer and the potential of these compounds to release nitric oxide (NO). S‑Nitrosothiols were synthesized by esterification reactions, using chlorides of the corresponding carboxylic acids, with good yields (~60%). IR results showed that these compounds presented only one conformation, and the experimental data were supported by the theoretical results obtained by density functional theory (DFT) calculations using the 6311+G (2df, 2p) basis set. The calculations revealed that all S‑nitrosothiols presented one preferential anticlinal (ac) geometric conformation, which agrees with the data obtained experimentally in CCl4. These conformers are stabilized by intramolecular hydrogen bonds. Examination of the geometry with regard to the RSNO group revealed that these compounds are preferentially in the trans (anti) conformation. The calculation of the orbital interactions using the Natural Bond Orbital (NBO) method showed that the nO(NO) → σ(SN)∗ hyper-conjugative interaction increases the SN bond length. The strong nS → π(NO)∗ interaction and electronic delocalization induces a partial π character to the SN bond. The weak σSN bond indicates strong delocalization of the electron pair in O (NO) by the nO(NO) → σ(SN)∗ interaction, thereby increasing the capacity of NO release from SNO-ESTERS.


Genome wide microarray based expression profiles associated with BmNPV resistance and susceptibility in Indian silkworm races of Bombyx mori.
The molecular mechanism involved in BmNPV resistance was investigated using a genome wide microarray in midgut tissue of Indian silkworm Bombyx mori. In resistant race (Sarupat), 735 genes up-regulated and 589 genes down-regulated at 12 h post BmNPV infection. Similarly, in case of susceptible race (CSR-2), 2183 genes up-regulated and 2115 genes down-regulated. Among these, nine up-regulated and eight down-regulated genes were validated using real-time qPCR analysis. In Sarupat, vacuolar protein sorting associated, Xfin-like protein and carboxypeptidase E-like protein genes significantly up-regulated in infected midgut; prominently down-regulated genes were glutamate receptor ionotropic kainite 2-like, BTB/POZ domain and transferrin. Considerably up-regulated genes in the CSR-2 were peptidoglycan recognition protein S6 precursor and rapamycin while the conspicuous down-regulated genes were facilitated trehalose transporter and zinc transporter ZIP1-like gene. The up-regulation of genes in resistant race after BmNPV infection indicates their possible role in antiviral immune response.


Integration of functional brain information into stereotactic irradiation treatment planning using magnetoencephalography and magnetic resonance axonography.
To minimize the risk of neurologic deficit after stereotactic irradiation, functional brain information was integrated into treatment planning. Twenty-one magnetoencephalography and six magnetic resonance axonographic images were made in 20 patients to evaluate the sensorimotor cortex (n = 15 patients, including the corticospinal tract in 6), visual cortex (n = 4), and Wernicke's area (n = 2). One radiation oncologist was asked to formulate a treatment plan first without the functional images and then to modify the plan after seeing them. The pre- and postmodification values were compared for the volume of the functional area receiving > or =15 Gy and the volume of the planning target volume receiving > or =80% of the prescribed dose. Of the 21 plans, 15 (71%) were modified after seeing the functional images. After modification, the volume receiving > or =15 Gy was significantly reduced compared with the values before modification in those 15 sets of plans (p = 0.03). No statistically significant difference was found in the volume of the planning target volume receiving > or =80% of the prescribed dose (p = 0.99). During follow-up, radiation-induced necrosis at the corticospinal tract caused a minor motor deficit in 1 patient for whom magnetic resonance axonography was not available in the treatment planning. No radiation-induced functional deficit was observed in the other patients. Integration of magnetoencephalography and magnetic resonance axonography in treatment planning has the potential to reduce the risk of radiation-induced functional dysfunction without deterioration of the dose distribution in the target volume.


[Colorectal cancer as surgical emergency].
295 out of 3014 patients (9.8%) treated for colorectal carcinoma between 01/1969 and 12/1983 presented as emergencies. The postoperative mortality rate of 28% was high in the emergency group compared with 6% after elective surgery. The tumor stage was far more advanced with 27% distant metastases. The overall 37% 5-year-survival rate was significantly different from that after elective operations (57%, p.o. deaths not included). Differences were statistically not significant when respective UICC-stages were compared.


Flexible protein database based on amino acid k-mers.
Identification of proteins is one of the most computationally intensive steps in genomics studies. It usually relies on aligners that do not accommodate rich information on proteins and require additional pipelining steps for protein identification. We introduce kAAmer, a protein database engine based on amino-acid k-mers that provides efficient identification of proteins while supporting the incorporation of flexible annotations on these proteins. Moreover, the database is built to be used as a microservice, to be hosted and queried remotely.


Ultrasensitive electrochemical DNA detection based on dual amplification of circular strand-displacement polymerase reaction and hybridization chain reaction.
We developed a novel electrochemical strategy for ultrasensitive DNA detection using a dual amplification strategy based on the circular strand-displacement polymerase reaction (CSDPR) and the hybridization chain reaction (HCR). In this assay, hybridization of hairpin-shaped capture DNA to target DNA resulted in a conformational change of the capture DNA with a concomitant exposure of its stem. The primer was then hybridized with the exposed stem and triggered a polymerization reaction, allowing a cyclic reaction comprising release of target DNA, hybridization of target with remaining capture DNA, polymerization initiated by the primer. Furthermore, the free part of the primer propagated a chain reaction of hybridization events between two DNA hairpin probes with biotin labels, enabling an electrochemical reading using the streptavidin-alkaline phosphatase. The proposed biosensor showed to have very high sensitivity and selectivity with a dynamic response range through 10fM to 1nM, and the detect limit was as low as 8fM. The proposed strategy could have the potential for molecular diagnostics in complex biological systems.


Can CT-based assessment of lateral malleolus anatomy indicate when and how to perform an intramedullary fixation in distal fibula fractures? An analysis of 150 ankles.
The primary aim was to analyse the lateral malleolus morphology with a focus on the shape of the distal fibula for IM fixation of the fibula in infra- and transsyndesmotic fracture patterns. The secondary aim was to propose a treatment algorithm according to the lateral malleolar anatomy. 77 healthy, skeletally mature volunteers underwent CT scanning of the ankle. The fibula medullary canal and its cortical thickness were quantitatively analysed at 4 different levels measured from the fibular tip (1.5 cm, 3.0 cm, 4.5 cm, and 6.0 cm). A geometric classification was proposed, and a decision algorithm was developed. Statistical significance was set at a p-value < 0.05. The smallest diameter of the medullary canal of the fibula was at 6.0 cm from the tip of the fibula, in 98.2% of the ankles. The distal fibula can be classified into triangular and rectangular type, according to the cortical thickness index (p < 0.0001). In 16.7% ankles, the internal diameter of the fibula at 6.0 cm was equal or narrower than 3.5 mm (p < 0.05). The shape of the distal fibula as evaluated by CT-guided analysis allows for IM osteosynthesis of the lateral malleolus in 83% of individuals. In our study, the smallest diameter of the medullary canal of the fibula was located 6.0 cm from the tip of the lateral malleolus. Coronal CT evaluation is advantageous in indicating which type of IM implant should be used safely for infra- and transsyndesmotic fracture patterns, potentially reducing intraoperative risks.


Movement and persistence of aldicarb in certain soils.
When the rate of movement and the persistence of aldicarb in 4 types of soils were investigated in laboratory and field studies some leaching was detected in coarse sand; however, leaching was quite limited in clay loam and muck soils. These data indicated that aldicarb degraded quite rapidly in the selected soils and most of the applied radioactivity volatilized from these soil columns as 14CO2. The evolution of 14CO2 from the treated soil suggested severe degradation of the aldicarb molecule and consequently provided indirect evidence against the accumulation of significant quantities of toxic metabolites in the soil types evaluated. Under field conditions this toxicant appeared to have a half-life of about 7 days in loam soil.


Noninvasive methods for haemoglobin screening in prospective blood donors.
The haemoglobin level of prospective blood donors is usually performed on blood obtained by from the finger pulp by fingerstick with a lancet and filling a capillary tube with a sample. New noninvasive methods are now available for rapid, noninvasive predonation haemoglobin screening. Prospective blood donors at our blood centre were tested, in two different trials, as follows: by the NBM 200 (OrSense) test (n = 445 donors) and by the Pronto-7 (Masimo) test (n = 463 donors). The haemoglobin values of each trial and the haemoglobin of finger pulp blood obtained by fingerstick with a lancet (HemoCue) were compared with the haemoglobin values obtained from a venous sample on a Cell Counter (Beckman Coulter). Comparison of Beckman Coulter Cell Counter and OrSense and results showed a bias of 0.29 g/dl, the standard deviation of the differences (SDD) of 0.98 and 95% limits of agreement from -1.64 to 2.21, using Bland and Altman statistical methodology. Comparison of Masimo and Beckman Coulter Cell Counter results showed a bias of -0.53 g/dl, SDD of 1.04 and 95% limits of agreement from -2.57 to 1.51. Cumulative analysis of all 908 donors, as tested by the usual fingerstick test showed a bias of 0.83 g/dl, SDD of 0.70 and 95% limits of agreement from -0.54 to 2.20 compared with the Coulter Cell Counter. Compared with the Coulter Counter, the specificity of the methods was 99.5% for fingerstick, 97% for OrSense and 83% for Massimo, and the sensitivity was 99, 98 and 93%, respectively. Analysis of finger pulp blood by either direct sampling by fingerstick and Hemocue, or by noninvasive haemoglobin tests does not replicate the results of cell counter analysis of venous samples. Compared with fingerstick, noninvasive haemoglobin tests eliminate pain and reduce stress, but have a lower level of specificity and sensitivity.


Angiographic features in tubular-papillary adenocarcinoma of the kidney.
Angiography and nephrotomography are essential in evaluation of avascular or hypovascular space occupying lesions of the kidney. Ultrasound adds another dimension in differentiating solid from cystic masses. Two cases of tubular-papillary adenocarcinoma were reported. Their angiographic findings consisted of a few neovascularities. Nephrotomography and ultrasonography in the second case showed a solid mass.


Induction of a step in carcinogenesis that is normally associated with mutagenesis by nonmutagenic concentrations of 5-azacytidine.
The permanent cell line BHK-21/cl 13 can be transformed by mutagenic carcinogens as the result of the induction of a recessive somatic mutation. Yet when these cells were treated with 5-azacytidine under conditions in which no mutants resistant to either ouabain or 6-thioguanine could be detected, they were transformed efficiently. These transformants were induced, not selected. 6-Azacytidine was ineffective at transforming BHK cells; 2'-deoxy-5-azacytidine was exceptionally effective. When tested by cell fusion, transformants induced by 5-azacytidine fell into the same complementation group as those induced by highly mutagenic carcinogens, but they were phenotypically distinct in that they were unstable during prolonged passage and rarely displayed the temperature-limited phenotypes so common among BHK transformants induced by strongly mutagenic carcinogens. These results raise the possibility that a cell can be induced by either genetic or epigenetic means to traverse the same single step in carcinogenesis.


Fibrosing cholestatic hepatitis in a renal transplant recipient associated with the hepatitis B virus precore mutant.
A patient with evidence of chronic infection with hepatitis B virus (seropositive for hepatitis B surface antigen, and with antibody to hepatitis B e antigen) underwent renal transplantation, which subsequently failed. The patient developed abnormal liver function tests and 8 months after the removal of the transplanted kidney, hepatitis B virus DNA was detected in the serum in the absence of hepatitis B e antigen. Liver biopsy revealed the presence of fibrosing cholestatic hepatitis. Sequence analysis of the serum hepatitis B virus DNA showed the presence of the pre-core mutant. This case shows that fibrosing cholestatic hepatitis can occur outside the setting of liver transplantation, and coincided with the development of the pre-core mutant of hepatitis B virus.


Frailty: emergence and consequences in women aged 65 and older in the Women's Health Initiative Observational Study.
To define frailty using simple indicators; to identify risk factors for frailty as targets for prevention; and to investigate the predictive validity of this frailty classification for death, hospitalization, hip fracture, and activity of daily living (ADL) disability. Prospective study, the Women's Health Initiative Observational Study. Forty U.S. clinical centers. Forty thousand six hundred fifty-seven women aged 65 to 79 at baseline. Components of frailty included self-reported muscle weakness/impaired walking, exhaustion, low physical activity, and unintended weight loss between baseline and 3 years of follow-up. Death, hip fractures, ADL disability, and hospitalizations were ascertained during an average of 5.9 years of follow-up. Baseline frailty was classified in 16.3% of participants, and incident frailty at 3-years was 14.8%. Older age, chronic conditions, smoking, and depressive symptom score were positively associated with incident frailty, whereas income, moderate alcohol use, living alone, and self-reported health were inversely associated. Being underweight, overweight, or obese all carried significantly higher risk of frailty than normal weight. Baseline frailty independently predicted risk of death (hazard ratio (HR)=1.71, 95% confidence interval (CI)=1.48-1.97), hip fracture (HR=1.57, 95% CI=1.11-2.20), ADL disability (odds ratio (OR)=3.15, 95% CI=2.47-4.02), and hospitalizations (OR=1.95, 95% CI=1.72-2.22) after adjustment for demographic characteristics, health behaviors, disability, and comorbid conditions. These results support the robustness of the concept of frailty as a geriatric syndrome that predicts several poor outcomes in older women. Underweight, obesity, smoking, and depressive symptoms are strongly associated with the development of frailty and represent important targets for prevention.


Use of DMSO for the cryopreservation of Tritrichomonas foetus in liquid nitrogen.
Four Tritrichomonas foetus strains were successfully preserved in liquid nitrogen at -196 degrees C in the presence of 10% dimethylsulfoxide (DMSO) for 7 months (Strain 1) and 6 months (Strain 2, 3 and 4). The percentage of viable organisms after thawing ranged between 65 and 85%, depending upon the strain. The method used is described in detail.


Effect of 60 Hz electromagnetic fields on the activity of hsp70 promoter: an in vitro study.
We have evaluated the effect of 60 Hz sinusoidal magnetic fields (MF) at 8 and 8 microT on expression of the luciferase gene contained in a gene construct labelled as Electromagnetic Field-plasmid (pEMF). The vector included the hsp70 promotor containing the 3 nCTCTn sequences previously described for the induction of hsp70 expression by magnetic fields, as well as the reporter of the luciferase gene. We also replicated the study of Lin et al. [Lin H, Blank M, Rossol-Haseroth K, Goodman R. Regulating genes with electromagnetic response elements. J Cell Biochem 2001;81(1):143-48]. The pEMF plasmid was transfected into HeLa and BMK16 cell lines that were later exposed to either MF or thermal shock (TS). An increased luciferase expression was found in both the cells exposed to MF and TS compared with their control groups (P < 0.05). Furthermore, the combined effect of MF and TS was also analyzed. A synergistic effect between two factors was observed for this co-exposure condition in terms of luciferase gene expression.


Association of pro-fibrinolytic receptor AnnexinA2 with tissue plasminogen activator/Inhibitor-1 in pre-eclampsia.
The clinical manifestations of pre-eclampsia are related to placental anti-angiogenic factor alteration. These variations are mainly due to the alteration of plasminolytic components. The study aims to compare the expression of plasminolytic components in the placenta of women with and without pre-eclampsia. The study included pregnant women with pre-eclampsia as PE group (n = 30) and without pre-eclampsia as a control group (n = 30). Placental bed biopsy tissues were collected. AnxA2, tPA, PAI-1 expression in the placental villous tissue was quantitatively evaluated using immunohistochemistry, western blot, and real time-PCR analysis. The results of the study showed a significant decrease in the expression of ANXA2 and increased expression of tPA and PAI-1 in PE group compared to control group (p<0.005). AnxA2 expression showed positive correlation with tPA (r=+0.895, p=0.002) and negative correlation with PAI-1(r=-0.905, p=0.020) in control group whereas in the PE group AnxA2 expression was negatively correlated with tPA ((r=-0.801, p=0.016) and PAI-1 (R=-0.831, P=0.010). Decreased AnxA2 with increased expression of PAI-1 and tPA may be responsible for the altered fibrinolytic activity and play a significant role in pre-eclampsia pathogenesis.


Effects of the speed ratio on the efficiency of planetary mills.
The ignition time (tig) of the mechanically induced self-sustaining reaction (MSR) process involving the formation of TiB2 from Ti/2B elemental mixtures was used to study the influence of the ratio (k = -ω v /ω d ) between the rotational speed of the supporting disc (ω d ) and vials (ω v ) on the milling efficiency of a Pulverisette 4 planetary mill. The variation of the inverse of the ignition time (1/tig), which is directly related to the milling power provided by the planetary mill, with the process conditions has shown that it is not possible to find a single k value as optimal independently of the experimental conditions used (ω d and the ball-to-powder ratio, BPR). Moreover, it was observed that the lowest milling efficiency (longer tig values) was found for k = 1, which is the usual value employed in routine laboratory works. The best efficiencies were found for the larger k values (2.5 or 3). At lower ω d, the shortest tig was obtained for k = 2.5 and at higher ω d for k = 3, independently of BPR.


[A case of MPO-ANCA positive hypertrophic pachymeningitis associated with vascular inflammation in the kidney biopsy].
We report a 76-year-old male with ANCA-associated hypertrophic pachymeningitis, who presented with crescentic glomerulonephritis. At the initial visit, he had episodic frontal headache and multiple cranial nerve palsy, including double vision, right deafness, hoarseness, and dysphagia. Because proteinuria and hematuria were detected on urinalysis, we performed a kidney biopsy, leading to the diagnosis of crescentic glomerulonephritis. The presence of vascular inflammation in the kidney biopsy led us to consider that this patient may show progression to the systemic type of MPO-ANCA-positive hypertrophic pachymeningitis. This proved useful for prognostic and treatment determination. Based on the results of laboratory tests, imaging studies, and biopsies of the dura mater and kidney, the patient was diagnosed with ANCA-associated hypertrophic pachymeningitis.


Use of magnetic resonance cholangiography in the diagnosis of choledocholithiasis: prospective comparison with a reference imaging method.
Magnetic resonance cholangiography (MRC) is a new technique for non-invasive imaging of the biliary tract. To assess the results of MRC in patients with suspected bile duct stones as compared with those obtained with reference imaging methods. 70 patients (34 men and 36 women, mean (SD) age 71 (15.5) years; median 75) with suspected bile duct stones were included (cholangitis, 33; pancreatitis, three; suspected post-cholecystectomy choledocholithiasis, nine; cholestasis, six; stones suspected on ultrasound or computed tomography scan, 19). MR cholangiograms with two dimensional turbo spin echo sequences were acquired. Endoscopic retrograde cholangiography with or without sphincterotomy (n = 63), endosonography (n = 5), or intraoperative cholangiography (n = 2) were the reference imaging techniques used for the study and were performed within 12 hours of MRC. Radiologists were blinded to the results of endoscopic retrograde cholangiography and previous investigations. 49 patients (70%) had bile duct stones on reference imaging (common bile duct, 44, six of which impacted in the papilla; intrahepatic, four; cystic duct stump, one). Stone size ranged from 1 to 20 mm (mean 6.1, median 5.5). Twenty seven patients (55%) had bile duct stones smaller than 6 mm. MRC diagnostic accuracy for bile duct lithiasis was: sensitivity, 57.1%; specificity, 100%; positive predictive value, 100%; negative predictive value, 50%. Stones smaller than 6 mm are still often missed by MRC when standard equipment is used. The general introduction of new technical improvements is needed before this method can be considered reliable for the diagnosis of bile duct stones.


Synthesis, transformation and biological evaluation of 2,3-secotriterpene acetylhydrazones and their derivatives.
It has been previously shown that semi-synthetic A-secotriterpene acetylhydrazones of 1-cyano-28-methoxy-28-oxo-2,3-seco-2-norlup-20(29)-en-3-al and 1-cyano-2,3-seco-2-nor-19β,28-epoxy-18αH-olean-3-al (1, 2) inhibit the vesicular stomatitis virus (VSV) replication. To improve the antiviral activity against VSV, structural modifications of compounds 1 and 2 were performed, and new A-secoderivatives containing the acetylhydrazone fragment were obtained from betulonic acid and its methyl ester, allobetulone, and 3-oxo-18βH-glycyrrhetinic acid methyl ester. The inhibitory effects of these compounds on VSV replication in porcine embryo kidney (PEK) cells were determined after infection. It was shown that introduction of the 3'-acetyl-5'-methyl-1',3',4'-oxadiazoline fragment into lupane triterpene structures lead to an increase in the antiviral activity of A-secotriterpene derivatives. However, the presence of a heterocyclic moiety enhanced toxic activity and reduced the therapeutic indices of these agents. Investigation in the anti-proliferative activity of the heterocyclic derivatives has shown high sensitivity of A-549, MS and RD tumor cell lines to lupane (R)-oxadiazoline 11a. The pro-apoptotic effect of 11a was confirmed by the AnnexinV/PI analysis.


Attitude, preventive practice and perceived barriers among perioperative and anesthesia nurses toward surgical smoke hazards during the COVID-19 outbreak.
Surgical smoke (SS), which is produced by the use of high-temperature devices for cutting and coagulation of tissue during surgical procedures, is considered a serious threat to the health of operating room (OR) staff due to the presence of hazardous substances and possibility of transmitting various infections such as HPV, HIV, COVID-19 and so on. This study was conducted to determine the Attitude, preventive practice and perceived barriers among perioperative and anesthesia nurses toward surgical smoke hazards. In this cross-sectional descriptive study, conducted at hospitals of Tabriz University of Medical Sciences (Iran) in 2021, 262 perioperative and anesthesia nurses were included by stratified random sampling. Data were collected using a demographic questionnaire and an SS questionnaire consisting of questions on attitude (17 item), practice (8 item), and barriers (13 item). Collected data were analyzed using SPSS16. The mean attitude and preventive practice scores (49.52 ± 12.36 and 15.8 ± 2.05, respectively) of the operating room nurses were reported at moderate and weak levels, respectively. There was a direct and significant relationship between attitude and practice scores (r = 0.129, P = 0.019). The main barriers to the prevention and dealing with the hazards of SS in ORs were reported in management (3.68 ± 1.06) and equipment (3.24 ± 0.66) dimensions, respectively. It is recommended to adopt strategies to improve the attitude of OR staff regarding the preventive measures against surgical smoke hazards. Moreover, appropriate equipment and support of managers should be provided by explaining the policies and guidelines to prevent the complications of surgical smoke.


Integrated analysis of topoisomerase I inhibitors from flavonoids of Scutellaria baicalensis Georgi using bioaffinity ultrafiltration UPLC-TripleTOF MS/MS, molecular docking and target-based multiple complex networks.
Scutellaria baicalensis Georgi (SBG) has been widely used as medical plant in East Asia with remarkable anti-cancer activity. However, the underlying mechanisms are still confused. In this study, an integrated analysis was conducted to screen topoisomerase I (topo I) inhibitors from flavonoids of SBG and investigate the anti-cancer mechanisms, containing bioaffinity ultrafiltration UPLC-ESI-TripleTOF-MS/MS, molecular docking, and multiple complex networks. The SBG extract exhibited notable cytotoxic activity on Hela cells. Five flavonoids were identified as potential topo I inhibitors, including skullcapflavone II, wogonin, chrysin, oroxylin A, and tenaxin I. Their ESI-MS/MS spectra showed that RDA reaction and neutral molecule loss were the main fragment patterns. Docking results demonstrated that π-π interaction and the formation of hydrogen bond contributed most to their binding with topo I. The selected compounds, related target proteins and pathways were integrated into target-based multiple complex networks, which consisted of three subnetworks. Statistical and topological analysis of these networks revealed a series of characteristics, including scale-free property with power-law degree distribution, Poisson degree distribution, and small-world property. Chrysin, wogonin, and oroxylin A exhibited as main active components with much higher degree values. Chemical carcinogenesis-receptor activation (hsa05207) was considered as critical pathway due to remarkable centrality indexes. Additionally, potential synergistic effect of wogonin and chrysin was observed on the conversion of supercoiled DNA to relaxed forms. These results improved current understanding of flavonoid-rich plants on the treatment of cancer. Moreover, the multi-disciplinary approach provided a new strategy for the research of natural products from medical plants.


Tests for host-associated fitness trade-offs in the milkweed-oleander aphid.
The milkweed-oleander aphid, Aphis nerii (Boyer de Fonscolombe) (Homoptera: Aphididae), feeds on different milkweed species in northern California than in Puerto Rico. The hosts vary, primarily between regions, for both identity and quantity of cardenolides that the aphid sequesters for its own defense. In tests for hostassociated fitness trade-offs only one case was found in which host plant and fitness corresponded, but the effect was not significant. However, power to detect fitness trade-offs was limited and the possibility of considerable differences in fitness on a particular host for aphids from different hosts cannot be excluded. On Californian host species, among which migration is common, generalized host use could result from selection for general-purpose genotypes. However, this explanation cannot apply to generalized host use of Californian and Puerto Rican milkweeds because the regions are isolated by distance. A cardenolide sequestration mechanism that is free of substantial energy costs could provide the basis for fitness homeostasis on variable host plants that makes trade-offs unlikely even on hosts from different regions.


Evaluation of Retinal Ganglion Cell via Visual Evoked Potential.
Visual Evoked Potential (VEP) is an electrical signal recorded from the visual cortex in response to light stimulation. It can be used as an in vivo method to objectively access the functional integrity of the retinogeniculocortical pathway. Here we describe the methods to perform flash VEP (FVEP) recording in rodents and goat and pattern VEP (PVEP) recording in rhesus macaque.


Expression of SERK family receptor-like protein kinase genes in rice.
Some SERK-family receptor-like protein kinase genes have been shown to confer embryonic competence to cells. In this study, we isolated two novel rice genes, OsSERK1 and OsSERK2, belonging to the SERK-family. OsSERK2 showed constitutive expression. The OsSERK1 promoter showed reporter gene activities in some specific tissues in a germinating seed, leaf and root, but not in a developing embryo. This promoter activity suggests that OsSERK1 may have roles in non-embryonic tissues rather than in the embryo.


Effect of site-directed mutagenesis of conserved aspartate and arginine residues upon farnesyl diphosphate synthase activity.
All polyprenyl synthases catalyze the condensation of the allylic substrate, isopentenyl diphosphate, with a specific homoallylic diphosphate substrate. Polyprenyl synthases from Homo sapiens, Ratus rattus, Escherichia coli, Saccharomyces cerevisiae, Neurospora crassa, and Erwinia herbicola contain two conserved "aspartate-rich domains" (Ashby, M.N., and Edwards, P.A. (1992) J. Biol. Chem. 267, 4128-4136). In order to determine the importance of these domains in catalysis, the conserved aspartates or arginines in domains I and II of rat farnesyl diphosphate synthase were individually mutated to glutamate or lysine, respectively. The putative "active site" arginine (Brems, D.N., Breunger, E., and Rilling, H. C. (1981) Biochemistry 20, 3711-3718) was mutated to lysine. Each mutant enzyme was overexpressed in E. coli and purified to apparent homogeneity. Detailed kinetic analyses of the wild type and mutant enzymes indicated that mutagenesis of Asp104, Asp107, Arg112, Arg113, and Asp243 resulted in a decreased Vmax of approximately 1000-fold compared to wild type. However, no significant change in the Km values for either the isopentenyl diphosphate or geranyl diphosphate substrate were observed. The results strongly suggest that these amino acids, and to a lesser extent Asp244, are involved in either the condensation of isopentenyl diphosphate and geranyl diphosphate to form farnesyl diphosphate and/or the release of the farnesyl diphosphate product from farnesyl diphosphate synthase. The conservation of these amino acid residues in different enzymes from several species suggests that these domains play a similar role in other polyprenyl synthases.


Structure and dynamics of neural network oscillators.
Techniques are given to represent oscillating neural networks by asynchronous logical switching networks, and to analyze the oscillating networks using a directed graph called a state transition diagram. Consideration is restricted to network oscillators containing no rhythm determining pacemaker neurons, and no neurons exhibiting self-limiting properties such as post-inhibitory rebound or accumulating refractoriness. In the state transition diagrams, stable oscillations are associated with a particular geometric configuration called a cyclic attractor (the heavy cycle in Fig. 2). We show that given the network connectivity it is possible to predict autonomous dynamic behaviour, as well as behaviour following hyperpolarizing or depolarizing inputs to neurons of the network. Conversely, given information about patterns of firing activity during cycles and transients of neural networks, the network connectivity can be predicted. The theoretical techniques can be used to generate a census of network structures capable of generating stable oscillations. Several representative network oscillators are discussed in the context of previous theoretical and experimental studies of the structure of neural network oscillators. Although the number of theoretically possile network oscillators capable of generating sustained oscillations is very large, the techniques which are given should be useful in the design of experiments capable of distinguishing between equally plausible hypotheses.


Prevalence and risk factors for severe linezolid-associated thrombocytopenia in pediatric patients: An analysis of a public database.
Linezolid is widely used in various clinical settings. Studies have revealed that it may cause thrombocytopenia in adults. However, the correlation between the use of linezolid and thrombocytopenia in pediatric patients is still unclear. This study aimed to identify the impact of Linezolid on the occurrence of thrombocytopenia in children. A retrospective observational study was conducted using data on patients treated with linezolid from the Pediatric Intensive Care clinical database. Univariate and multiple logistic regression analyses were performed to identify the risk factors of linezolid-related severe thrombocytopenia. A total of 134 patients were included. The prevalence of severe thrombocytopenia was 8.96% (12/134). Univariate analysis indicated that the severe thrombocytopenia group showed significantly higher proportion of concomitant carbapenem (75% vs 44.3%; P < .05) and piperacillin/tazobactam (25% vs 6.6%; P < .05) than that of the non-severe thrombocytopenia group. Multivariate analysis also revealed that the occurrence of severe thrombocytopenia was significantly associated with concurrent use of carbapenem (odd ratio = 4.058; 95% confidence interval: 1.012-16.274; P = .048) and piperacillin/tazobactam (odd ratio = 5.335; 95% confidence interval: 1.117-25.478; P = .036). 75% of patients (9/12) developed severe thrombocytopenia within the first 7 days of linezolid use. The concomitant use of carbapenem and piperacillin/tazobactam was associated with an increased probability of severe thrombocytopenia in pediatric patients undergoing linezolid treatment. Further prospective clinical studies are required, and more detailed mechanisms of blood toxicity in pediatric patients must be investigated.


Multiple renal calculi due to hypercalcaemia induced by over-the-counter vitamin D intoxication.
Renal stone disease is a common and painful condition. Even though it is rarely fatal, patients describe it as the worst pain in their life. While dietary calcium may decrease the risk of stone formation, patients on supplemental calcium are at higher risk. Moreover, patients with diabetes are more prone to develop renal calculi. Hypervitaminosis D is a rare cause of hypercalcaemia. This is a case of an elderly diabetic man who developed multiple calcium oxalate renal stones due to hypercalcaemia following calcium-vitamin D supplementation.


Cell death in the skin: how to study its quality and quantity?
The characterization of the quality and quantity of cell death has gained substantial interest over the past decades. More recently necroptosis as a programmed form of necrosis has been identified as an important additional form of cell death with relevance in the skin. Understanding how to assay cell death in specific is of critical importance for cancer research and treatment. Here we describe six different methods that can be used to assay cell viability and to study the quality or quantity of cultured human keratinocytes in vitro. These methods include crystal violet assay, hypodiploidy analysis, caspase-8 cleavage, release of HMGB1, annexin V/propidium iodide co-staining, and Hoechst/SYTOX green co-staining.


In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes.
To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer's disease.


Neuronal cytoskeletal lesions induced in the CNS by intraventricular and intravenous aluminium maltol in rabbits.
The antigenicity of neuronal cytoskeletal lesions was studied immunohistochemically in adult New Zealand white rabbits after intraventricular (subacute) and intravenous (chronic) administration of a water-soluble aluminium compound, aluminium (Al) maltol. After short-term intraventricular administration, rabbits developed widespread neurofibrillary degeneration (NFD) involving pyramidal neurons of the isocortex and allocortex, projection neurons of the diencephalon, and nerve cells of the brain stem and spinal cord. There was a predilection for motor neuron involvement and for the infratentorial portions of the neuraxis. Perikarya and proximal neurites were especially affected. Bundles of 10 nm filaments were frequently present. Three of the animals treated intravenously for 12 weeks or longer displayed NFD in the oculomotor complex and in the pyramidal neurons of the occipital isocortex. Following either mode of administration, the affected neurons exhibited immunostaining with a panel of monoclonal antibodies (MAbs) against phosphorylated (SMI-31), non-phosphorylated/phosphatase-sensitive (SMI-32), and dephosphorylation-independent (SMI-33) epitopes of high and middle molecular weight neurofilament (NF) protein subunits. They were non-reactive with MAbs to microtubule-associated protein 2 and the class III neuron-associated beta-tubulin isotype. Our findings indicate that intraventricular Al maltol produces similar, but more widespread degeneration of projection-type neurons than the less water-soluble Al compounds as reported by others. The NFD lesions are compared with those of senile dementia of the Alzheimer type (SDAT) and motor neuron disease.


Changes in depression status during the year after breast cancer surgery and impact on quality of life and functioning.
Although breast cancer patients' depression changes over time, most longitudinal studies have assessed the influence of only baseline depression on quality of life (QoL). Therefore, this study investigated the influence of changes in depression status on QoL in the year after surgery. Participants were interviewed at 2-5days and at 1year after surgery. Depression was diagnosed at both time points, and participants were classified into four groups: no, recovered, incident, and persistent depression. QoL-related functioning and symptoms were evaluated with the EORTC QLQ-C30 questionnaire and the interaction of depression and QoL was analyzed using a repeated-measures analysis of covariance (RMANCOVA). Of the 306 participants, 247 were evaluated at 1year after surgery; 165 had no depression, 40 had recovered from depression, 24 had incident depression, and 18 had persistent depression. The RMANCOVA revealed significant time-by-group interactions; the no-depression group exhibited better recovery in general QoL and functioning, whereas the persistent-depression group showed the worst recovery. QoL and functioning improved in the recovered depression group, but worsened in the group with incident depression. The different impacts of changes in depression status on QoL highlight the importance of periodic screening for depression.


Probenecid-induced changes in the clearance of carprofen enantiomers: a preliminary study.
Probenecid inhibits the elimination of several acidic drugs. In this study, the influence of probenecid on the pharmacokinetics of carprofen was investigated in three healthy volunteers after single peroral administration of 150 mg of RS-(+/-)-carprofen. Carprofen enantiomers and their glucuronides (after cleavage with sodium hydroxide) were measured by use of a stereospecific procedure. The plasma concentrations of S-(+)-carprofen were higher than those of R-(-)-carprofen at most of the sampling points. Probenecid reduced apparent total and renal clearances for both enantiomers. It also reduced the clearances of the carprofen enantiomers to their glucuronides and the renal clearances of the glucuronides. The differences caused by probenecid were significant, but few stereoselective effects were observed.


Vitamin D and Calcium Supplement Use and High-Risk Breast Cancer: A Case-Control Study among BRCA1 and BRCA2 Mutation Carriers.
The role of vitamin D and calcium use in the development of breast cancer among women in the general population is not clear. Furthermore, whether vitamin D and calcium supplement use are associated with breast cancer in high-risk populations has not been evaluated. Thus, we evaluated the association between vitamin D and/or calcium supplement use and breast cancer among women with a pathogenic variant (mutation) in BRCA1 or BRCA2. BRCA mutation carriers enrolled in a longitudinal study were invited to complete a supplemental questionnaire on lifetime supplement use. Cases included women with a prevalent diagnosis of invasive breast cancer, and controls had no history of breast cancer. Vitamin D and calcium use were categorized as never/ever use, and as tertiles of supplement intake (total average daily supplement use). Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of breast cancer. This study included 134 breast cancer cases and 276 controls. Women who used vitamin D-containing supplements had 46% lower odds of having breast cancer compared to those who never used supplements (OR 0.54; 95% CI 0.31, 0.91; p = 0.02). Increasing vitamin D and calcium supplement intake was inversely associated with the odds of having breast cancer (p-trend = 0.04). Findings were suggestively stronger among BRCA1 mutation carriers; however, analyses were limited by small strata. These findings suggest a potential inverse association between vitamin D and calcium supplementation and BRCA breast cancer. Additional studies are warranted to confirm these findings and accurately inform clinical care guidelines.


New technique for endoscopic treatment of bleeding gastric ulcer.
In two patients with bleeding gastric ulcer hemorrhage could be stopped by submucous infiltration around the lesion without any complication. This simple method using a selfconstructed needle seems to guarantee good results especially in bleeding little arteries. Infiltration was performed with a 1.5% solution of Aethoxysklerol (Kreussler, Wiesbaden-Biebrich) using 3-5 ml totally for treatment.


Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment.
To clarify the clinical features of systemic lupus erythematosus (SLE) complicated with pulmonary hypertension (PH) and to evaluate the efficacy of immunosuppressive treatment. Case records were reviewed for 194 patients with SLE who were admitted to Aoyama Hospital of Tokyo Women's Medical University between 1992 and 1999. There were 12 patients with PH [8 SLE and 4 SLE + systemic sclerosis (SSc) overlap syndrome]. These patients were compared with 59 age and sex matched patients with SLE for clinical characteristics and laboratory findings. The efficacy of treatments for PH was also evaluated. In our cohort of 194 patients with SLE, 6.2% had PH. The plasma thrombin-antithrombin III complex and plasma D-dimer levels were significantly higher in patients with PH compared with those without PH. Eight patients with PH (4 SLE and 4 SLE + SSc) were treated with corticosteroids (CS) +/- cyclophosphamide (CYC). Right ventricular systolic pressure (RVSP) was improved in 7 of 8 patients. In 6 of 7 responders to the therapy, the treatment was started as soon as they were diagnosed with PH. PH relapsed in 2 patients treated with oral CS +/- CS pulse therapy, but their RVSP was decreased again by immunosuppressive treatment. CS +/- CYC was effective for PH associated with SLE. Immunosuppressive treatment should be performed during the early stage of PH to improve prognosis.


Disentangling the seasonal co-occurrence patterns and ecological stochasticity of planktonic and benthic bacterial communities within multiple lakes.
Both the planktonic bacterial community (PBC) and benthic bacterial community (BBC) are important for biogeochemical processes in freshwater lakes. Despite their ecological significance, little is known about their seasonal co-occurrence patterns and the ecological processes that drive them. In this study, we aimed to investigate the ecological associations among bacterial taxa and assembly processes of PBC and BBC in different seasons. We used 16S rRNA gene high-throughput sequencing of a total of 150 water and sediment samples collected from multiple lakes distributed in an urban region of China during winter and summer. Our results revealed that PBC showed stronger seasonal variations in co-occurrence patterns than BBC, suggesting that BBC had greater temporal stability than PBC. Winter PBC network was characterized by higher connectivity and complexity, and thereby the formation of a highly stable community structure; whereas lower connectivity arising from the presence of fewer predicted keystone taxa (hubs and connectors in a network) was destabilizing to summer PBC network. In addition, the phylum Firmicutes identified as a putative keystone taxon of PBC in both seasons played a non-negligible role in maintaining network structure which may result from strong functional associations with other bacterioplankton. Temperature and pH were the best explanatory factors predicting the seasonal co-occurrence patterns of PBC and BBC, respectively. Normalized stochasticity ratio based on null-model analysis indicated that deterministic processes overwhelmed stochastic processes in governing the assembly of PBC and BBC in both seasons. However, we observed a greater influence of ecological stochasticity on BBC assembly than PBC assembly in both seasons. Taken together, these findings provide insights into understanding the impacts of habitat heterogeneity and seasonal variability on microbial assemblage patterns in lake ecosystems.


Peritoneal closure reduces port site metastases: results of an experiment in a rat ovarian cancer model.
The arm of this study was to assess the role of peritoneal closure in the prevention of port site metastasis after carbon dioxide (CO2) CO2 pneumoperitoneum. We developed a xenograft ovarian cancer model by intraperitoneal injection of 27 106 IGR-OV1 line cells in nude rats Seven days after the inoculation, the animals underwent a CO2 pneumoperitoneum. At the end of the procedure, port sites were randomly closed either with suture of peritoneum (n = 14, group A) or without suture of peritoneum (n = 12, group B). The rats were killed 7 days after surgery and their port site scars were resected. Tumor implantation was assessed by a pathologist who was blinded to the type of wound closure. The animals in group B were significantly more likely to have at least one port site metastasis frequent (seven of 12, or 58.3%) than those in group A (two of 14, or (14.3%) (p = 0.037). Port sites with metastases were seen more frequently in group B (eight of 24, or (33.3%) than in group A (three of 28, or 10.7%) (p = 0.046). Our results shows that peritoneum closure decreases the risk of port site metastasis.


Compositional analysis of the three main gangliosides from adult human myometrium by a rapid capillary gas chromatographic method.
A new capillary GC method is described for the compositional analysis of the three main gangliosides isolated from adult human myometrium. The sample was subjected to methanolysis, acetylation and trimethylsilylation which allows all the constituents to be analyzed simultaneously. The predominant ganglioside was found to be GD3, with GM3 and GT1b the next most abundant.


Particle Localization Using Local Gradients and Its Application to Nanometer Stabilization of a Microscope.
Particle localization plays a fundamental role in advanced biological techniques such as single-molecule tracking, superresolution microscopy, and manipulation by optical and magnetic tweezers. Such techniques require fast and accurate particle localization algorithms as well as nanometer-scale stability of the microscope. Here, we present a universal method for three-dimensional localization of single labeled and unlabeled particles based on local gradient calculation of particle images. The method outperforms state-of-the-art localization techniques in high-noise conditions, and it is capable of 3D nanometer accuracy localization of nano- and microparticles with sub-millisecond calculation time. By localizing a fixed particle as fiducial mark and running a feedback loop, we demonstrate its applicability for active drift correction in sensitive nanomechanical measurements such as optical trapping and superresolution imaging. A multiplatform open software package comprising a set of tools for local gradient calculation in brightfield, darkfield, and fluorescence microscopy is shared for ready use by the scientific community.


The effect of papaverine on acute opiate withdrawal in guinea pig ileum.
In the present work the effect of papaverine, a non specific smooth muscle relaxant, was investigated on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum in vitro. Furthermore, the effect of papaverine was also considered on DAGO (highly selective mu -agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of papaverine on opioid withdrawal involves mu - and/or k-opioid receptors. Following a 4 min in vitro exposure to opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. Papaverine treatment (1 x 10(-7) - 5 x 10(-7) - 1 x 10(-6) M) before or after the opioid agonists was able of both preventing and reversing the naloxone-induced contracture after exposure to mu (morphine and DAGO) or k (U50-488H) opiate agonists in a concentration-dependent fascion. Both acetylcholine response and electrical stimulation were not affected by papaverine treatment whereas the final opiate withdrawal was still reduced. The results of the present study indicate that papaverine was able to produce significative influence on the opiate withdrawal in vitro and papaverine was able to exert its effect both at mu and k opioid agonists.


Initial single-center experience using Fiber Optic RealShape guidance in complex endovascular aortic repair.
In the present study, we have described the technical success using Fiber Optic RealShape (FORS) endovascular guidance and its effects on the overall procedural time and radiation usage during complex endovascular aortic repair (EVAR). Fenestrated and branched EVARs performed at a single center from 2017 to 2022 were prospectively studied. FORS-guided procedures were matched retrospectively 1:3 to non-FORS-guided procedures by the incorporated target arteries and body mass index. Technical success was defined as successful target vessel cannulation using FORS for the entirety of navigation (wire insertion to exchange for a stiff wire). The predictors of technical success were evaluated via logistic regression. The procedural times and radiation doses were compared between the matched cohorts using the Wilcoxon rank sum test. A total of 21 FORS-guided procedures were matched to 61 non-FORS-guided procedures. A total of 95 FORS cannulations were attempted (87 for the visceral target artery and 8 for the bifurcate gate). Technical success was achieved in 81 cannulations (85%); 15 (16%) were completed without the use of live fluoroscopy. The univariate predictors of FORS technical success included <50% target artery stenosis, <50% target artery calcification, and the target vessel attempted (P < .05 for each). FORS failures were attributed to device material properties in six cases, device failure in two cases, and the wire/catheter combination in six. The use of FORS guidance was associated with shorter median procedural and fluoroscopy times and a lower dose area product and air kerma (P ≤ .0001 for each). The results from our initial experience with FORS during complex EVAR, including our learning curve, has shown promise, with acceptable technical success and reductions in procedural times and radiation usage.


Development of Chronic Pseudomonas aeruginosa-Positive Respiratory Cultures in Children with Tracheostomy.
Up to 90% of children develop Pseudomonas aeruginosa (Pa)-positive respiratory cultures after tracheotomy. To identify the factors associated with chronic Pa-positive respiratory cultures in the first 2 years after tracheotomy. We conducted a retrospective cohort study of 210 children ≤ 18 years old who underwent tracheotomy at a single freestanding children's hospital that had two or more years of respiratory cultures post-tracheotomy available for analysis. We conducted multivariable logistic regression to test the association between demographic and clinical factors to our primary outcome of chronic Pa infection, defined as > 75% of respiratory cultures positive for Pa in the first 2 years after tracheotomy. Of the primarily male (61%), Hispanic (68%), and publicly insured (88%) cohort, 18% (n = 37) developed chronic Pa-positive respiratory cultures in the first 2 years. On multivariable logistic regression, pre-tracheotomy Pa-positive respiratory culture (aOR 11.3; 95% CI 4-1.5) and discharge on beta agonist (aOR 6.3; 95% CI 1.1-36.8) were independently associated with chronic Pa-positive respiratory cultures, while discharge on chronic mechanical ventilation was associated with decreased odds (aOR 0.3; 95% CI 0.1-0.7). On sensitivity analysis examining those without a pre-tracheotomy Pa-positive respiratory culture, discharge on MV continued to be associated with decreased odds of chronic Pa (aOR 0.1; 95% CI 0.02-0.4) and three other variables (male gender, chronic lung disease, and discharge on inhaled corticosteroids) were associated with increased odds of chronic Pa. Because pre-tracheotomy Pa growth on respiratory culture is associated with post-tracheotomy chronic Pa-positive respiratory cultures, future research should examine pre-tracheotomy Pa eradication or suppression protocols.


Insulin autoantibodies at the clinical manifestation of type 1 (insulin-dependent) diabetes--a poor predictor of clinical course and antibody response to exogenous insulin.
To study the possible clinical significance of the appearance of insulin autoantibodies prior to the diagnosis of Type 1 (insulin-dependent) diabetes, and their value in predicting the antibody response to exogenous insulin, we observed 46 newly diagnosed diabetic children and adolescents over the year following diagnosis for the occurrence and duration of clinical remission, daily insulin dose, metabolic control, residual B-cell function, insulin-binding antibodies and conventional as well as complement-fixing islet cell antibodies. Insulin-binding antibodies were determined using both monoiodinated human and porcine insulin. Sixteen children (34.7%) were positive for insulin autoantibodies upon diagnosis of Type 1 diabetes. These subjects were significantly younger (6.2 +/- 1.0 versus 10.8 +/- 0.8 years; mean +/- SEM, p less than 0.001), and their haemoglobin A1 levels were lower (14.1 +/- 0.6 versus 16.0 +/- 0.8%, p less than 0.05) at diagnosis than in the insulin autoantibody negative group. There were no significant differences in the occurrence and duration of clinical remission between insulin autoantibody-positive and -negative test groups. Daily insulin dose, haemoglobin A1 and serum C-peptide concentrations were of the same magnitude in both groups after the diagnosis, and no association could be found between the presence of insulin autoantibodies at diagnosis and persistently positive islet cell antibodies. In tests conducted 3 months after diagnosis, the group of patients with insulin autoantibodies showed significantly higher levels (p less than 0.05) of antibodies binding human insulin than the group negative for insulin autoantibodies, but no significant differences could be found between the insulin binding titres of the two groups in subsequent analyses.(ABSTRACT TRUNCATED AT 250 WORDS)


Design of the ZWOT-CASE study: an observational study on the effectiveness of an integrated programme for cardiovascular risk management compared to usual care in general practice.
Cardiovascular diseases (CVD) contribute considerably to mortality and morbidity. Prevention of CVD by lifestyle change and medication is important and needs full attention. In the Netherlands an integrated programme for cardiovascular risk management (CVRM), based on the Chronic Care Model (CCM), has been introduced in primary care in many regions in recent years, but its effects are unknown. In the ZWOT-CASE study we will assess the effect of integrated care for CVRM in the region of Zwolle on two major cardiovascular risk factors: systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-cholesterol) in patients with or at high risk of CVD. This study is a pragmatic observational study comparing integrated care for CVRM with usual care among patients aged 40-80 years with CVD (n = 370) or with a high CVD risk (n = 370) within 26 general practices. After 1 yr follow-up, primary outcomes (SBP and LDL-cholesterol level) are measured. Secondary outcomes include lifestyle habits (smoking, dietary habits, alcohol use, physical activity), risk factor awareness, 10-year risk of cardiovascular morbidity or mortality, health care consumption, patient satisfaction and quality of life. The ZWOT-CASE study will provide insight in the effects of integrated care for CVRM in general practice in patients with CVD or at high CVD risk. The ZWOlle Transmural Integrated Care for CArdiovaScular Risk Management Study; ClinicalTrials.gov ; Identifier: NCT03428061; date of registration: 09-02-2018; This study has been retrospectively registered.


Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model.
The contribution of chronic tobacco exposure in determining post-myocardial infarction (MI) left ventricular (LV) remodeling and possible therapeutic strategies has not been investigated systematically. In this small animal investigation, we demonstrate that chronic tobacco smoke exposure leading up to acute MI in rats is associated with greater histological extent of myocardial necrosis and consequent worse LV function. These findings are associated with increased transcriptomic expression of pro-inflammatory cytokines, tissue repair molecules and markers of oxidative stress in the myocardium. The results demonstrate that an N-acetyl cysteine (NAC) treatment significantly reduced tobacco-exposed induced infarct size and percent fractional shortening. A significantly increased LV end-systolic diameter was observed in tobacco-exposed sham compared to tobacco-naïve sham (4.92±0.41 vs 3.45±0.33; P<0.05), and tobacco-exposed MI compared to tobacco-naïve MI (8.24±0.3 vs 6.1±0.49; P<0.01) rats. Decreased intracardiac mRNA expression of the markers of inflammation, tissue repair and oxidative stress and circulating levels of pro-inflammatory cytokines accompanied these positive effects of NAC. The treatment of tobacco-exposed MI rats with NAC resulted in significantly increased levels of intracardiac mRNA expression of antioxidants, including superoxide dismutase, thioredoxin and nuclear factor-E2-related factor 2, as well as circulating levels of glutathione (7±0.12 vs 10±0.18; P≤0.001), where the levels were almost identical to the tobacco-naïve sham rats. These findings identify a novel post-infarction therapy for amelioration of the adverse effects of tobacco exposure on the infracted myocardium and advocate the use of dietary supplement antioxidants for habitual smokers to prevent and reverse cardiovascular adverse effects in the absence of successful achievement of cessation of smoking.


Inclusion of Olecranon Osteotomy With the Posterior Approach for Fixation of Distal Humerus Fractures (OTA/AO 13) Does Not Increase Surgical Complications.
To determine if inclusion of an olecranon osteotomy to the posterior paratricipital approach for operative fixation of distal humerus fractures significantly affects surgical complication rates (OTA/AO 13). Retrospective comparative cohort study. Level 1 trauma center. Three hundred four patients underwent open reduction internal fixation of a distal humerus fracture between 2007 and 2017. Of those, 134 met inclusion criteria (≥15 years, OTA/AO fracture type 13A, B, or C, and posterior surgical approach) for the study (n = 64 with olecranon osteotomy; n = 70 without olecranon osteotomy). Open reduction internal fixation of distal humerus fractures performed using a posterior paratricipital approach with or without olecranon osteotomy. Ulnar neuropathy (UN), fracture site bony nonunion, and surgical site infection (SSI). Thirty-one (33.3%) who underwent the paratricipital approach without olecranon osteotomy, and 15 patients (26.8%) who underwent olecranon osteotomy reported postoperative UN with no significant difference between approaches (P = 0.438). There was no significant difference in rates of SSI (P = 0.418) or fracture site nonunion (P = 0.263) when comparing the approaches. Subjects with Charlson comorbidity index ≥2 were more likely to not undergo an olecranon osteotomy (P = 0.01), whereas subjects with more complex fractures by OTA/AO classification were more likely to have an olecranon osteotomy approach (P = 0.001). Addition of an olecranon osteotomy with the paratricipital approach for fixation of distal humerus fractures does not result in higher rates of UN, fracture site nonunion, or SSI. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Design of aquifer remediation systems: (2) estimating site-specific performance and benefits of partial source removal.
A Lagrangian stochastic model is proposed as a tool that can be utilized in forecasting remedial performance and estimating the benefits (in terms of flux and mass reduction) derived from a source zone remedial effort. The stochastic functional relationships that describe the hydraulic "structure" and non-aqueous phase liquid (NAPL) "architecture" have been described in a companion paper (Enfield, C.G., Wood, A.L., Espinoza, F.P., Brooks, M.C., Annable, M., Rao, P.S.C., this issue. Design of aquifer remediation systems: (1) describing hydraulic structure and NAPL architecture using tracers. J. Contam. Hydrol.). The previously defined functions were used along with the properties of the remedial fluids to describe remedial performance. There are two objectives for this paper. First, is to show that a simple analytic element model can be used to give a reasonable estimate of system performance. This is accomplished by comparing forecast performance to observed performance. The second objective is to display the model output in terms of change in mass flux and mass removal as a function of pore volumes of remedial fluid injected. The modelling results suggest that short term benefits are obtained and related to mass reduction at the sites where the model was tested.


Ropy slime formation in vacuum-packed cooked meat products caused by homofermentative lactobacilli and a Leuconostoc species.
This paper deals with the cause of the formation of ropy slime on the surface of vacuum-packed cooked meat products. Two different homofermentative lactobacilli and a Leuconostoc strain were isolated from different ropy vacuum-packed meat products. The strains were able to produce slime experimentally on vacuum-packed cooked sausages. The slime had a molecular weight in the range of 70000-30000 and contained glucose and galactose in a ratio 10:1-10:2. The formation of ropy slime also occurred on sausages without added sugars.


Distinct aggregate stratification of antibiotic resistome in farmland soil with long-term manure application.
Agricultural soils, which are closely linked to human health via food supply, have been recognized as an important reservoir for antibiotic resistance genes (ARGs). However, there is still a lack of knowledge regarding the role of soil aggregates in shaping ARG profile. In this study, we collected soils from long-term experimental farmland plots receiving inorganic and/or organic fertilizers and examined the patterns of antibiotic resistome distribution among differently sized soil aggregates using high-throughput quantitative polymerase chain reaction (HT-qPCR). Our results showed that the distribution of soil ARGs could be affected by manure application and aggregate size individually but not interactively. More diverse and abundant ARGs were found in the manured soils, compared to the non-manured soils. The aggregate size fraction of <53 μm exhibited the highest diversity and abundance of ARGs. Variation partitioning analysis revealed that soil traits, mobile genetic elements, and bacterial community collectively contributed to the variation of soil antibiotic resistance. The knowledge about aggregation stratification of soil ARGs obtained in this study is fundamental and essential to understanding the fate of soil ARGs at the microscale.


Decreased beta-cell function in overweight Latino children with impaired fasting glucose.
To determine whether overweight Latino children with impaired fasting glucose (IFG) (> or = 100 mg/dl) have increased insulin resistance or decreased beta-cell function compared with those with normal fasting glucose (NFG). We studied 207 healthy overweight Latino children, aged 8-13 years, with a family history of type 2 diabetes. Fasting and 2-h glucose and insulin were assessed by oral glucose tolerance test. Insulin sensitivity (S(i)), the acute insulin response to glucose (AIRg), and the disposition index (DI; an index of beta-cell function) were determined using the insulin-modified intravenous glucose tolerance test and minimal modeling. Body composition was determined by dual-energy X-ray absorptiometry. There were no differences in body composition between NFG (n = 182) and IFG (n = 25) children. Compared with children with NFG, children with IFG had higher fasting and 2-h glucose values and higher fasting insulin. After adjusting for covariates, children with IFG had no difference in S(i) but 15% lower DI than NFG children (2,224 +/- 210 vs. 2,613 +/- 76, P < 0.05). Multivariate linear regression showed that AIRg and DI, but not S(i), were significant predictors of fasting blood glucose. In overweight Latino adolescents with a family history of type 2 diabetes, IFG is associated with impaired beta-cell function and therefore may identify children likely to be at risk for progression to type 2 diabetes. The actual risk of progression of IFG to type 2 diabetes remains to be determined by prospective longitudinal studies.


MicroRNA-7a inhibits Isl1 expression to regulate insulin secretion by targeting Raf1 and Mapkap1 in NIT-1 cells.
Both microRNA-7a (miR-7a) and LIM-homeodomain transcription factor ISL1 are important factors regulating insulin transcription and secretion, but the functional relationship and the interacting mechanisms between miR-7a and ISL1 in pancreatic islet β-cells remain unknown. The aims of this study were thus to identify the potential interactions and signaling communication between miR-7a and ISL1 in regulating insulin transcription and secretion in the cultured NIT-1 cells. The results show that miR-7a inhibitor upregulates Isl-1 and insulin gene expressions, and the insulin secretion. Whereas miR-7a mimics inhibit ISL1 and insulin gene expressions, and decreases the insulin secretion. Furthermore, we identified the target gene of miR-7a using dual-luciferase reporter assay, and the results demonstrate that Raf1 and Mapkap1 is a direct target gene of miR-7a, modeling RAF1/MEK/ERK1/2 and mTORC2/AKT signaling pathway to regulate Isl1 expression, and thus influencing insulin expression and secretion. Our results indicate that therapeutic inhibition of miR-7a function could be of relevance for preserving the function of pancreatic β-cells during the course of diabetes development, implicating miR-7, ISL1, and/or the connecting molecules may act as novel targets for pharmacological or gene therapy in diabetes and related metabolic disease, although much detailed studies are required in the further study.


Primary perianal actinomycosis. Report of a case and review of the literature.
A case of primary perianal actinomycosis presenting as recurrent perianal abscesses is reported. Although this is a rare presentation of actinomycosis, it is easily recognized when encountered and should be treated with surgical drainage, examination under anesthesia, and long-term antibiotic therapy.


Axonal synapse sorting in medial entorhinal cortex.
Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges.