Identification of components of Prunus africana extract that inhibit lipid peroxidation.
Extractive and chromatographic separations were performed on V-1326, a chloroform extract from the bark of Prunus africana (also referred to as Pygeum africanum), which is used to treat the symptoms associated with benign prostate hyperplasia (BPH). The relative amounts of eleven identified constituents in crude V-1326 and in separated fractions were determined using gas chromatographic analysis. The ability of V-1326 and its separated fractions to inhibit ferrous ion-induced stimulation of lipid peroxidation in microsomal preparations from rabbit livers was evaluated. The extract, V-1326, and fractions containing high levels of myristic acid potently inhibited lipid peroxidation.


Pyrrolnitrin and related pyrroles endowed with antibacterial activities against Mycobacterium tuberculosis.
During development of nitroheterocycles with potential antimycobacterial activities we have tested against Mycobacterium tuberculosis a number of pyrroles strictly related to pyrrolnitrin, an antifungal antibiotic isolated from Streptomyces pyrrocinia. Some of the tested arylpyrrole derivatives and pyrrolnitrin have shown appreciable inhibiting activity against M. tuberculosis and M. avium. SAR studies well correlate antimycobacterial potency with the presence of halogens in the phenyl ring and a nitro group at position 3 of pyrrole.


The efficacy of platelet-rich plasma gel in MRSA-related surgical wound infection treatment: an experimental study in an animal model.
The wound healing properties of platelet-rich plasma (PRP) gel have been documented in many studies. PRP gel has also become a promising agent for treating surgical site infections. In this study, we investigated the antibacterial activity and wound healing effectiveness of PRP in an animal model of Methicillin-resistant Staphylococcus aureus subsp. aureus (MRSA N315)-contaminated superficial soft tissue wounds. Subcutaneous wounds in Wistar Albino male rats were created by making two cm midline incisions followed by inoculation of microorganisms. Study groups comprised of Sham (no treatment), PRP alone, MRSA alone, MRSA + PRP, MRSA + Vancomycin, and MRSA + Vancomycin + PRP groups. We inoculated 0.1 mL (3 × 108 CFU/mL) of MRSA in contaminated groups. After 8 days, all rats were killed, wounds were excised and subjected to histopathologic examination, and MRSA counts were determined. MRSA counts in MRSA, MRSA + PRP, MRSA + Vancomycin and MRSA + Vancomycin + PRP groups were 5.1 × 106 (SD ± 0.4) CFU/mL, 4.3 × 106 (SD ± 0.7) CFU/mL, 2.3 × 106 (SD ± 0.3) CFU/mL, 1.1 × 106 (SD ± 0.4) CFU/mL, respectively. The inflammation scores of MRSA + PRP, MRSA + Vancomycin, and MRSA + Vancomycin + PRP groups were significantly lower than the MRSA group. MRSA + Vancomycin + PRP group inflammation score was significantly lower than the MRSA + PRP group. All treatment groups were effective in wound healing and decreasing the MRSA counts. MRSA + PRP combined created identical inflammation scores to the PRP group. More in vivo studies are required to corroborate these findings.


Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events.
Diabetic neuropathy is a dying back neurodegenerative disease of the peripheral nervous system where mitochondrial dysfunction has been implicated as an etiological factor. Diabetes (type 1 or type 2) invokes an elevation of intracellular glucose concentration simultaneously with impaired growth factor support by insulin, and this dual alteration triggers a maladaptation in metabolism of adult sensory neurons. The energy sensing pathway comprising the AMP-activated protein kinase (AMPK)/sirtuin (SIRT)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) signaling axis is the target of these damaging changes in nutrient levels, e.g., induction of nutrient stress, and loss of insulin-dependent growth factor support and instigates an aberrant metabolic phenotype characterized by a suppression of mitochondrial oxidative phosphorylation and shift to anaerobic glycolysis. There is discussion of how this loss of mitochondrial function and transition to overreliance on glycolysis contributes to the diminishment of collateral sprouting and axon regeneration in diabetic neuropathy in the context of the highly energy-consuming nerve growth cone.


Improving monitoring for metabolic syndrome using audit.
Audit has been defined as "a quality improvement process that seeks to improve patient care and outcome, through systematic review of care and comparison with explicit criteria, followed by the implementation of change". As of May 2011, under the Medical Practitioners Act 2007, doctors are legally obliged to join in professional competence schemes, following requirements set by the Medical Council. These include the obligation for doctors to conduct one clinical audit per year. In Ireland and elsewhere, audit provides an opportunity for services to create an "environment in which clinical care will flourish".


A sensitive and rapid mass spectrometric method for the simultaneous measurement of eight steroid hormones and CALIPER pediatric reference intervals.
To develop an accurate assay and establish the normal reference intervals for serum cortisol, corticosterone, 11-deoxycortisol, androstenedione, 21-hydroxyprogesterone, testosterone, 17-hydroxyprogesterone, and progesterone. These steroids are commonly used as biomarkers for the diagnosis and monitoring of endocrine diseases such as congenital adrenal hyperplasia. Appropriate age- and gender-stratified reference intervals are essential in accurate interpretation of steroid hormone levels. The samples analyzed in this study were collected from healthy, ethnically diverse children in the Greater Toronto Area as part of the CALIPER program. A total of 337 serum samples from children between the ages of 0 and 18years were analyzed. The concentrations were measured by using an LC-MS/MS method. The data were analyzed for outliers and age- and gender-specific partitions were established prior to establishing the 2.5th and 97.5th percentiles for the reference intervals. Reference intervals for all hormones required significant age-dependent stratification while testosterone and progesterone required additional sex-dependent stratification. We report a sensitive, accurate and relatively fast LC-MS/MS method for the simultaneous measurement of eight steroid hormones. Detailed reference intervals partitioned based on both age and gender were also established for all eight steroid hormones.


Neural correlates of perceptual priming of visual motion.
In two experiments, the temporal dynamics of neural activity underlying perceptual priming of visual motion was examined using event-related potentials (ERPs) during directional judgments of the apparent motion of two-dimensional sine-wave gratings. Compared to perceptually ambiguous motion, unambiguous left- or rightward motion was associated with enhanced ERP activity about 300 ms after the onset of apparent motion. In the second experiment, ERPs were recorded to two successive motion jumps in which an unambiguous motion jump served as a prime for a subsequent target motion that was ambiguous. The prime-target time interval was varied between 200, 400, and 1000 ms. In a control (motion reversal) condition, the two motion jumps were both unambiguous but in opposite directions. Compared to the motion reversal condition, motion priming was associated with an enhancement of ERP amplitudes at 100 ms and 350 ms following target stimulus onset. ERP enhancement was greatest at a short prime-target interval of 200 ms, which was also associated behaviorally with the strongest priming. The ERP enhancement and behavioral priming were both eliminated at the long 1000 ms prime-target interval. Functional magnetic resonance imaging (fMRI) data from a subset of subjects supported the view that motion priming involves modulation of neural responses both in early visual cortex and in later stages of visual processing.


To increase the incorporation efficiency of genetically encoding Nε-acetyllysine in recombinant protein.
Reversible Nε-lysine (Nε-Lys) acetylation is a dynamic post-translational modification. Genetic incorporation of Nε-acetyllysine (Nε-AcK) into the specific site of a protein is a powerful method for producing recombinant protein with acetylation and studying the functional role of protein acetylation. Because of the universal existence of deacetylase such as CobB in vivo, the acetyl group of Nε-AcK may be removed from recombinant protein. So in the process of incorporating acetyl lysine into protein, nicotinamide (NAM), a lysine deacetylase (KDAC) inhibitor, is needed to inhibit the KDAC activity and protect the acetyl group of Nε-acetyllysine incorporated from removal in vivo. In this study, we knocked out cobB gene from an E. coli strain and used it as host for incorporating of Nε-AcK into recombinant protein by expanding genetic code. Comparing with the addition of KDAC inhibitor, this is a novel method to protect the acetyl group of Nε-acetyllysine from deacetylation by using cobB knockout strain. Thus, this method provides a better way for protecting recombinant acetylated protein from deacetylation. By knocking out cobB gene from the strain of E. coli, we successfully produced homogeneous acetylated protein by expanding genetic code with a high effectiveness. This method will also provide a good reference for genetically introducing other varieties of modified amino acids into protein.


Subclinical giant cell arteritis in polymyalgia rheumatica: Concurrent conditions or a common spectrum of inflammatory diseases?
Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are common conditions in older adults. Their clinical connection has been recognized over time, with many patients experiencing both conditions separately, simultaneously or in temporal sequence to each other. Early GCA detection is essential to prevent vascular damage, but identifying subclinical GCA in PMR patients remains a challenge and routine screening is not standard practice. Subclinical GCA prevalence in newly diagnosed PMR patients ranges from 23 to 29%, depending on the screening method. Vessel wall imaging and temporal artery biopsy can detect subclinical GCA. Epidemiology and trigger factors show similarities between the two conditions, but PMR is more common than GCA. Genetic and pathogenesis studies reveal shared inflammatory mechanisms involving dendritic cells, pro-inflammatory macrophages, and an IL-6 signature. However, the inflammatory infiltrates differ, with extensive T cell infiltrates seen in GCA while PMR shows an incomplete profile of T cell and macrophage-derived cytokines. Glucocorticoid treatment is effective for both conditions, but the steroid requirements vary. PMR overall mortality might be similar to the general population, while GCA patients with aortic inflammatory aneurysms face increased mortality risk. The GCA-PMR association warrants further research. Considering their kinship, recently the term GCA-PMR Spectrum Disease (GPSD) has been proposed.


Primary orbital ganglioneuroma in a 2-year-old healthy boy.
A 2-year-old healthy child presented with progressive unilateral proptosis. general examination, detailed ophthalmic evaluation and radiological imaging were done. He underwent orbital exploration via anterior orbitotomy incision and debulking of the tumor was done. The histopathological examination confirmed the diagnosis of orbital ganglioneuroma. Ganglioneuroma is an unusual benign tumor of neuroplastic origin with extremely rare orbital involvement with only one prior reported case in a youth. The tumor is slow growing and non-metastasizing. Biopsy is necessary to differentiate it from the malignant neuroblastoma and excision is usually curative.


Structure and expression of oncogenes in surgical specimens of human breast carcinomas.
We have performed an analysis of ras, c-myc, c-myb, c-erbB1 and c-erbB2 oncogenes in 100 surgical samples of human breast carcinomas. No point mutations have been detected at the 12th codon of c-Ha-ras and c-Ki-ras in 40 and 65 breast cancer DNAs, respectively. One out of 65 samples showed a 50-fold amplification of c-Ha-ras that, however, was not overexpressed. Alterations in the structure of c-myc, c-myb c-erbB1 and c-erbB2 oncogenes were sporadically observed. In 20 tumour samples, the study of expression of a series of oncogenes revealed that c-Ha-ras was the predominantly transcribed gene among the ras gene family whereas c-fos appeared the most constantly and significantly expressed nuclear oncogene.


[Fetal acardia in a twin pregnancy achieved by in vitro fertilization].
The frequency of fetal arcadia in the world is 1:35,000 to 1:48,000 pregnancies; is currently estimated that 1% of newborns in developed countries are the result of assisted reproduction techniques and the frequency of twin pregnancies is close to 18%, of these, an estimated relative risk for cardiac defect is 1.6. However, the association of acardiac fetus, twin pregnancy and assisted reproductive techniques is not fully established. In this paper, we describe a case of fetal acardia, in a pregnancy resulting from assisted reproduction and its obstetric care.


Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study.
Serotonin 1A receptors (5-HT(1A)) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT(1A) and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT(1A) G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT(1A) than healthy volunteers (controls). We measure 5-HT(1A) in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. Genotyped and determined 5-HT(1A) binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. AN have higher 5-HT(1A) than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT(1A) receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT(1A).


The organization of motoneurons in the turtle lumbar spinal cord.
The distribution of motoneurons in the lumbosacral spinal cord of the turtle Pseudemys scripta elegans was studied by using the technique of retrograde transport of horseradish peroxidase. A total of 19 different hindlimb muscles were injected with varying amounts of horseradish peroxidase. The resulting distribution of labeled motoneurons was studied in both longitudinal and transverse sections of spinal cord. Motoneurons innervating a particular hindlimb muscle are clustered in longitudinally arranged motorpools. Motorpools of different muscles can show considerable overlap in both the rostrocaudal and transverse planes. The distribution of the various motorpools demonstrates a somatotopic organization of motoneurons within the lumbar spinal cord. Motoneurons innervating more distally positioned muscles are generally found in the more caudal segments, while motoneurons supplying proximal muscles are distributed throughout almost the whole lumbosacral intumescence. Motoneurons innervating anterodorsally positioned muscles are found in the ventrolateral part of area IX in the ventral horn, while more dorsomedially positioned motoneurons innervate the posteroventral muscles. These features are consistent with observations in other tetrapods, although the somatotopic representation of motoneurons is more evident in higher vertebrates such as chicken and cat. The observed motorpool distribution is discussed in relation to the presumed ontogeny of the spinal cord and hindlimb muscles and also in relation to the functions of the investigated muscles.


Occupational contact allergy to components of polyester resin systems.
Allergic contact dermatitis caused by polyester resin is considered to be rare. To describe 11 new patients diagnosed with occupational contact allergy to components of polyester resin systems in 1994-2009. Data on occupations, patch test results, symptoms and exposure to polyester products were retrieved from patient files, covering 1994 to February 2015. Five patients reacted to unsaturated polyester resin putties. In 3 of these cases, putties were considered to be the main cause of the dermatitis. Four patients had cobalt allergy resulting from cobalt salts that were used as accelerators in polyester resins. Three patients were sensitized to triglycidyl isocyanurate (TGIC), a cross-linker in polyester powder paints. Two product types are of particular importance in contact allergy to polyester resin: powder paints cured by heat with TGIC as the cross-linker, and car putties. Car putties are used not only in repair car painting, but also in some industrial trades to smoothen surfaces before painting. As commercial patch test substances of polyester resin putties are lacking, patients' own products need to be tested. Cobalt salts are used in several types of polyester resin product as accelerators, and these must be considered as a possible cause of cobalt sensitization.


Apoptosis-suppressing and autophagy-promoting effects of calpain on oridonin-induced L929 cell death.
Calpain, calcium-dependent cysteine protease, is reported here to impose the crucial influence on oridonin-induced L929 cell apoptosis and autophagy. We found that inhibition of calpain increased oridonin-induced Bax activation, cytochrome c release and PARP cleavage, indicating that calpain plays an anti-apoptotic role in oridonin-induced L929 cell apoptosis. To explore this potential anti-apoptotic mechanism, we inhibited calpain and proteasome activity in oridonin-induced L929 cell apoptosis, and discovered that the inducible IkappaBalpha proteolysis was partially blocked by the inhibition of either calpain or proteasome, but completely blocked by the inhibition of both. It demonstrated that calpain and proteasome were two distinct pathways participating in IkappaBalpha degradation. To further study the role of calpain in oridonin-induced L929 cell autophagy, we discovered that calpain inhibitor decreased oridonin-induced autophagy, as well as Beclin 1 activation and the conversion from LC3-I to LC3-II. Moreover, Inhibition of autophagy by 3-MA increased oridonin-induced apoptosis. In conclusion, besides suppressing apoptosis, calpain promotes autophagy in oridonin-induced L929 cell death, and inhibition of autophagy might contribute to up-regulation of apoptosis.


Screening cyclooxygenase-2 inhibitors from Allium sativum L. compounds: in silico approach.
Inflammation is a natural protective response toward various simulators, including tissue damage or pathogens. The cyclooxygenase-2 (COX-2) is a very important protein in triggering pain and inflammation. Previous studies have claimed that Allium sativum offers a wide range of anti-inflammatory therapeutics for human consumption. Drug discovery is a complicated process, though in silico methods can make this procedure simpler and more cost-effective. At the current study, we performed the virtual screening of eight Allium sativum-derived compounds via molecular docking with COX-2 enzyme and confirmed the binding energy by docking score estimate followed by ADMET and drug-likeness investigation. The resulting highest-docking scored compound was exposed to molecular dynamics simulation (MDS) for evaluating stability of the docked enzyme-ligand complex and to gauge the oscillation and conformational alterations for the time of enzyme-ligand interaction. The factors of RMSD, RMSF, hydrogen bond interactions, and Rg after 100 ns of MDS proved the stability of alliin in the active site of COX-2 in comparison with celecoxib (CEL) as the control. Moreover, we investigated the binding affinity analysis of all compounds via MM/PBSA method. The results from this study suggest that alliin (a sulfuric compound) exhibits a higher binding affinity for the COX-2 enzyme compared to the other compounds and CEL. Alliin showed to be a possible anti-inflammatory therapeutic candidate for managing the inflammatory conditions.


Effect of Acanthopanax senticosus stem on mast cell-dependent anaphylaxis.
We studied the effect of Acanthopanax senticosus stem (ACPS) on mast cell-dependent anaphylaxis. ACPS inhibited compound 48/80-induced systemic anaphylaxis at a dose of 1.0 g/kg by 50%. ACPS also inhibited passive cutaneous anaphylaxis reaction and histamine release from mast cells in a dose-dependent manner, respectively. Moreover, ACPS had an inhibitory effect on anti-dinitrophenyl IgE-induced tumor necrosis factor-alpha (TNF-alpha) production from mast cells. These results indicate that ACPS inhibits mast cell-mediated anaphylaxis in vivo and in vitro murine model.


Allergic conjunctivitis increases the likelihood of undergoing eyelid incision surgery in pediatric and adolescent patients.
The global prevalence of allergic diseases has increased dramatically in recent decades. From a global health perspective, they have been considered as a major chronic disease, and the related social burden has also been increasing worldwide. In line with this trend, we investigated the likelihood of undergoing incision surgery for eyelid inflammatory masses in pediatric and adolescent patients with allergic conjunctivitis (AC). The prevalence of AC and incision surgery showed a similar pattern of bimodal peaks during the spring and autumn of South Korea, reflecting the peak allergic seasons. The likelihood of undergoing incision surgery in patients with AC was 4.27 times higher than that of patients without AC and the likelihood of undergoing incision surgery was higher in every age group in the AC cohort than in the non-AC cohort. There was no significant difference between age groups and sexes. In the AC cohort for sub-analysis, the likelihood of undergoing incision surgery was 2.34 times higher in patients who used steroids than those who did not. These findings can suggest that proper management and education can be required for the likelihood of undergoing incision surgery due to eyelid inflammation mass in pediatric and adolescent patients with AC. Furthermore, greater attention should be paid to patients using steroids due to severe AC as they are more likely to undergo incision surgery.


Identification of nsLTP family in Chinese white pear (Pyrus bretschneideri) reveals its potential roles in russet skin formation.
Identification of PbLTP genes in pear and functional characterization of PbLTP4 in the transport of suberin monomers of russet skin formation. Non-specific lipid-transfer protein (nsLTP) is an abundant and diverse alkaline small molecule protein in the plant kingdom with complex and diverse biophysiological functions, such as transfer of phospholipids, reproductive development, pathogen defence and abiotic stress response. Up to now, only a tiny fraction of nsLTPs have been functionally identified, and the distribution of nsLTPs in pear (Pyrus bretschneideri) (PbLTPs) has not been fully characterized. In this study, the genome-wide analysis of the nsLTP gene family in the pear genome identified 67 PbLTP proteins, which could be divided into six types (1, 2, C, D, E, and G). Similar intron/exon structural patterns were observed in the same type, strongly supporting their close evolutionary relationship. In addition, PbLTP4 was highly expressed in russet pear skin compared with green skin, which was located in the plasma membrane. Coexpression network analysis showed that PbLTP4 closely related to suberin biosynthetic genes. The biological function of PbLTP4 in promoting suberification has been demonstrated by overexpression in Arabidopsis. Identification of suberin monomers showed that PbLTP4 promotes suberification by regulating 9,12-octadecadienoic acid and hexadecanoic acid transport. These results provide helpful insights into the characteristics of PbLTP genes and their biological function in the transport of suberin monomers of russet skin formation.


Efficiency and cost-effectiveness of advanced EMS in West Germany.
A model study was performed by an economist in Lower Frankonia (a mostly rural area of West Germany with several urban centers) to examine the efficiency and cost-effectiveness of the emergency medical service that included prehospital physician presence. To perform this examination about $3.5 million were spent to improve organization and communication within the local emergency medical service, to purchase additional equipment and further emergency vehicles, and to install prehospital emergency physician service. The median response time was lowered to 6 minutes. This report surveys whether these reforms and extra fundings were beneficial and cost-efficient.


Morphology of the complex laryngeal gland in the Atlantic bottlenose dolphin, Tursiops truncatus.
A complex lymphoepithelial gland is a constant feature in the larynx of Atlantic bottlenose dolphins, Tursiops truncatus, based on study of 56 animals. Larynges were removed from fresh, non-decomposed beach-stranded animals for gross examination and histological sampling. A large lymphoepithelial gland occurs in the rostro-ventral mucosa of the larynx, overlying the cricoid cartilage. It presents as a well-defined, elevated, and heavily trabeculated area. Histological examination reveals a pseudostratified columnar epithelium which branches into the underlying submucosa. The epithelial-lined folds and crypts thus formed are surrounded by aggregations of lymphocytes, which infiltrate this epithelium. Mucous glands are often associated with these lymphoid aggregations. The histological appearance of the laryngeal gland is remarkably similar to the palatine, or dorsal oropharyngeal tonsils, of T. truncatus. It may be analogous to the nasopharyngeal adenoid of terrestrial animals. Age-related involution of the laryngeal gland is not as obvious with increasing animal age (or length) as it is in other mucosa-associated lymphoid tissue. The distribution of this gland among cetaceans is not yet known. We have observed it in individuals of every species we have studied, including Lagenodelphis hosei, Stenella coeruleoalba, Stenella attenuata, Globicephala macrorhynchus, Steno bredanensis, Physeter catodon, Pseudorca crassidens, Mesoplodon europaeus, and Kogia breviceps.


Association of serum uric acid, morning home blood pressure and cardiovascular risk factors in a population with previous prehypertension: a cross-sectional study.
To observe the changes in blood pressure (BP) over 10 years and to investigate current BP association to serum uric acid (SUA) levels and cardiovascular risk factors in the epidemiological data of a target group of patients with prehypertension in 2007. Cross-sectional study. Mlati Subdistrict, Sleman District, Yogyakarta Province, Indonesia. A total of 733 patients from 'Mlati Study Database' in 2007 were selected by simple random sampling using statistical software. Subjects had both physical and laboratory examinations. Morning home BP and laboratory examination of urine (uric acid excretion and creatinine) and blood samples (SUA, blood urea nitrogen, creatinine, a lipid profile and fasting blood glucose levels). About 31.1% of 733 subjects with prehypertension became hypertensive after 10 years, 24.6% returned to normal tension and the rest of it remained in prehypertensive state. Mean (SD) of SUA levels in 2017 was significantly higher in men than in women (5.78 (1.25) mg/dL vs 4.52 (1.10) mg/dL, p<0.001). Furthermore, men tended to have high-normal (5-7 mg/dL) or high SUA levels (≥7 mg/dL) compared with women (p<0.001, Relative Risk (RR)=2.60). High-normal and high SUA levels in population with a history of prehypertension were significantly associated with current prehypertension and hypertension only in women (p=0.001, RR=1.21). Age and body mass index was found to be significantly associated with both systolic and diastolic BP in men, but only with systolic BP in women. Fasting blood glucose and SUA levels were significantly associated with systolic and diastolic BP only in women. We concluded that after 10 years, of 733 subjects with prehypertension, 31.1% became hypertensive. The SUA levels in men are significantly higher than those in women. Moreover, high-normal and high SUA levels were significantly associated with prehypertension and hypertension in women but not in men.


Fructus panax ginseng extract promotes hair regeneration in C57BL/6 mice.
Radix panax ginseng (Panax ginseng C.A. Meyer, Araliaceae, RPG) has been documented to possess hair growth activity and widely used to treat alopecia, while no report has been issued to date on the effect of Fructus panax ginseng (FPG) on hair regeneration. To investigate the effects of FPG extract on the proliferation of human hair dermal papilla cells (DPCs) and on the promotion of hair regeneration in C57BL6 mice, cell proliferation was evaluated in cultured DPC by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and measured the expressions of Bcl-2 and Bax by immunoblot assay. We also compared the effects of topical FPG extract (1 and 10 mg/ml, 100 μl/d) with the effects of minoxidil as a positive control (5%, 100 μl/d) or vehicle control (30% ethanol) on the depilation-induced hair cycling in 7 week-old-C57BL/6 mice. FPG extract significantly increased the proliferation of DPCs in dose and time dependent manners (P<0.05, P<0.01 and P<0.001). FPG extract also enhanced Bcl-2 expression and decreased Bax expression compared with control (P<0.01). Moreover, significant elongations of anagen phase during hair cycle after application of FPG were evaluated by photographical and histological observations. FPG extract improves the cell proliferation of human DPCs through anti apoptotic activation. Topical administration of FPG extract might have hair regeneration activity for the treatment of hair loss.


Recent advances in surgical strategies and liver transplantation for hepatoblastoma.
Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although the development of treatment strategies with advances in chemotherapy has greatly improved the prognosis of HB, surgical resection and liver transplantation still play a vital role in the treatment of HB. In recent years, technological innovations have led to the development of new surgical approaches for HB. In this review, we describe the latest research on the surgical management of HB, including new imaging technologies, minimally invasive approaches, and the application of associating liver partition portal vein ligation for staged hepatectomy. We also discuss the current role of liver transplantation, use of ante-situm or ex-situ liver resection with auto-transplantation, and management of metastatic HB.


Al-Cu-Fe quasicrystal/ultra-high molecular weight polyethylene composites as biomaterials for acetabular cup prosthetics.
Polymer composites of Al-Cu-Fe quasicrystals and ultra-high molecular weight polyethylene (UHMWPE) were investigated for use in acetabular cup prosthetics. The wear properties of the Al-Cu-Fe/UHMWPE samples and a 440 steel ball counterface were measured. The mechanical strength of the Al-Cu-Fe/UHMWPE composites was compared to UHMWPE and alumina/UHMWPE. The biocompatibility of the composite material was tested using a direct contact cytotoxicity assay. Al-Cu-Fe/UHMWPE demonstrated lower volume loss after wear and higher mechanical strength than UHMWPE. This composite material also showed no increase in counterface wear or cytotoxicity relative to UHMWPE. These combined results demonstrate that Al-Cu-Fe/UHMWPE composites are promising candidate materials for acetabular cup prosthetics.


[Heat inhibition of mastocyte degranulation in the nasal mucosa of the guinea pig].
Heating of Guinea-Pig nasal mucosa fragments during 30 min. at 43 degrees inhibits the degranulation of mast cells and the liberation of histamine. This accounts for the success of the thermotherapy of persistent allergic rhinitis.


Progress developing the concept of other effective area-based conservation measures.
In 2010, the introduction of other effective area-based conservation measures (OECMs) into international policy caused a paradigm shift in area-based conservation, which included consideration of areas outside formal protected areas and places where biodiversity conservation may not be a management objective for the site. Despite the importance of this shift for global conservation, conservation science and policy have been slow to engage with the concept of OECMs. As the world moves toward protecting 30% of the Earth by 2030, it is imperative to develop evidence-based guidance for how to identify effective conservation measures, especially tools to help evaluate and monitor the biodiversity outcomes associated with potential OECMs. To understand the current progress in developing the concept of OECMs, I evaluated the peer-reviewed literature to consolidate and synthesize current knowledge. I conducted a thematic analysis of papers to identify the types of challenges and opportunities being discussed and lessons from studies evaluating the effectiveness of OECMs. Only 105 studies mentioned OECMs, and those that did rarely move beyond superficial mention of OECMs as part of area-based conservation. Around one-half of studies listed potential risks or benefits of OECMs but none provided evidence these issues have materialized. Twenty-three studies attempted to identify potential OECMs, although specific case studies were rare. The 7 studies that evaluated existing OECMs were highly critical of how they had been implemented to date. Studies that evaluated conservation outcomes were extremely rare, and suggested effectiveness must be judged on a case-by-case basis. The current literature not only leaves many gaps in the science required to operationalize the concept of OECMs, but also often raises additional questions that need to be addressed. If these gaps are not filled by robust science, the promised benefits for biodiversity from OECMs may never be realized.


Isolation of Streptococcus milleri from clinical specimens.
During a period of 26 months, 80 strains of Streptococcus milleri were isolated from 80 patients with clinical evidence of infection. More than a third of the isolates were from lesions related to the gastro-intestinal tract and a quarter from abscesses of various other sites. The haemolytic activity and group antigenic profile of these isolates are discussed. In addition, the clinical significance of S. milleri isolated from various sites is evaluated.


Stereological and histopathological assessment of intrauterine growth restriction placenta from Saudi women.
Placental insufficiency causes fetal adaptation, leading to fetal programming of chronic diseases. Placentas with intrauterine growth restriction (IUGR) are smaller than average and may contribute to low birth weight of the newborn. The number of patients with IUGR in the Saudi population is increasing; however, little is known about their placentas. The aim of this study was to assess morphometric and histopathological placental changes in Saudi patients with IUGR. Overall, 20 healthy pregnant Saudi women (control group) and 20 pregnant Saudi women with IUGR were enrolled. Maternal and fetal morphometric measurements were recorded. The placentas from both groups were processed for histopathological examination using stereological techniques. The IUGR group had lower placental weight, volume, length, breadth, and surface area than the control group. The total volume of villi and surface area of the terminal villi were significantly reduced in the IUGR placentas. IUGR group had a reduction in birth weight; length; and circumference of the head, chest, abdomen, and thigh compared to control group. The reduction in placental mass, specifically the reduction in the volume and surface area of villi, the functional units, may have reduced the capacity for nutrient transport. This led to a significant reduction in neonatal measurements. The fetus rearranged nutrient distribution in favor of the brain and other essential organs; however, at the expense of thigh development and growth. This fetal trade-off strategy increases the risk of developing chronic diseases in adulthood. Therefore, IUGR infants may require more clinical attention.


Evaluation of hypotensive mechanisms of captopril in addition to its inhibition of the converting enzyme in spontaneously hypertensive rats.
In spontaneoulsy hypertensive rats (SHR), the hypotensive effect of captopril (30 mg/kg/day per os for 4 days), which inhibits the converting enzyme when given orally was significantly potentiated rather than suppressed by aprotonin (100,000 KIU/day s.c. for 7 days), but was not affected by indomethacin. These findings suggest that neither the kallikrein-kinin system nor the prostaglandin system is involved in any of the hypotensive actions of captopril in SHR other than the inhibition of the converting enzyme.


Antibodies Against Cleaved CDCP1 Show Activity in RAS-Mutant Tumors.
Targeting the proteolytically cleaved form of CDCP1 showed antitumor activity in solid tumor models.


Treatment as prevention in resource-limited settings: is it feasible to maintain HIV viral load suppression over time?
Recently, there has been increasing interest in the role of "treatment as prevention" (TasP). Some of the questions regarding TasP strategies arise from the perceived difficulties in achieving and maintaining viral load (VL) suppression over time and the risk of emergence of viral resistance that could compromise future treatment options. This study was conducted to assess these questions in a resource-limited setting. We performed a retrospective observational study of HIV-infected patients diagnosed in the pre-HAART era on follow-up at a private center from Buenos Aires, Argentina. Socio-demographic, clinical, and laboratory data were extracted from clinical charts. Analyses were performed to test for potential associations of selected variables with current virologic failure or use of third-line drugs. Of 619 patients on follow-up, 82 (13.2%) were diagnosed in the pre-HAART era. At the time of our study, 79 (96.3%) patients were on HAART, with a median duration of 14 years (IQR 12-15) of therapy, and exposure to mono or dual nucleoside reverse transcriptase inhibitors regimens in 47.8% of cases. Sixty-nine patients (87.3%) had undetectable VL, 37 (46.8%) never presented virologic failure, and 19 (24.1%) experienced only one failure. Thirteen patients (16.5%) were receiving third-line ART regimens, with an average of 2.7-fold more virologic failures than those on first- or second-line regimens (p = 0.007). Maintaining viral load suppression over time in resource-limited-settings is feasible.


GDNF-expressing macrophages restore motor functions at a severe late-stage, and produce long-term neuroprotective effects at an early-stage of Parkinson's disease in transgenic Parkin Q311X(A) mice.
There is an unmet medical need in the area of Parkinson's disease (PD) to develop novel therapeutic approaches that can stop and reverse the underlying mechanisms responsible for the neuronal death. We previously demonstrated that systemically administered autologous macrophages transfected ex vivo to produce glial cell line-derived neurotrophic factor (GDNF) readily migrate to the mouse brain with acute toxin-induced neuroinflammation and ameliorate neurodegeneration in PD mouse models. We hypothesized that the high level of cytokines due to inflammatory process attracted GDNF-expressing macrophages and ensured targeted drug delivery to the PD brain. Herein, we validated a therapeutic potential of GDNF-transfected macrophages in a transgenic Parkin Q311X(A) mice with slow progression and mild brain inflammation. Systemic administration of GDNF-macrophages at a severe late stage of the disease leaded to a near complete restoration of motor functions in Parkin Q311X(A) mice and improved brain tissue integrity with healthy neuronal morphology. Furthermore, intravenous injections of GDNF-macrophages at an early stage of disease resulted in potent sustained therapeutic effects in PD mice for more than a year after the treatment. Importantly, multiple lines of evidence for therapeutic efficacy were observed including: diminished neuroinflammation and α-synuclein aggregation, increased survival of dopaminergic neurons, and improved locomotor functions. In summary, GDNF-transfected macrophages represent a promising therapeutic strategy for PD at both late- and early-stages of the disease.


Emerging issues of connexin channels: biophysics fills the gap.
This summary is a proposed synthesis of available information for the non-specialist. It does not incorporate all the published data, is inconsistent with some, and reflects the biases of the author. Connexin proteins have a common transmembrane topology, with four alpha-helical transmembrane domains, two extracellular loops, a cytoplasmic loop, and cytoplasmic N- and C-terminal domains. The sequences are most conserved in the transmembrane and extracellular domains, yet many of the key functional differences between connexins are determined by amino-acid differences in these largely conserved domains. Each extracellular loop contains three cysteines with invariant spacing (save one isoform) that are required for channel function. The junctional channel is composed of two end-to-end hemichannels, each of which is a hexamer of connexin subunits. Hemichannels formed by some connexin isoforms can function as well-behaved, single-membrane-spanning channels in plasma membrane. In junctional channels, the cysteines in the extracellular loops form intra-monomer disulfide bonds between the two loops, not intermonomer or inter-hemichannel bonds. The end-to-end homophilic binding between hemichannels is via non-covalent interactions. Mutagenesis studies suggest that the docking region contains beta structures, and may resemble to some degree the beta-barrel structure of porin channels. The two hemichannels that compose a junctional channel are rotationally staggered by approximately 30 degrees relative to each other so that the alpha-helices of each connexin monomer are axially aligned with the alpha-helices of two adjacent monomers in the apposed hemichannel. At present there is a published 3D map with 7.5 A resolution in the plane of the membrane, based on electron cryomicroscopy of 2D crystals of junctional channels formed by C-terminal truncated Cx43. The correspondence between the imaged transmembrane alpha-helices and the known transmembrane amino-acid sequences is a matter of debate. Each of the approximately 20 connexin isoforms produces channels with distinct unitary conductances, molecular permeabilities, and electrical and chemical gating sensitivities. The channels can be heteromeric, and subfamilies among connexins largely determine heteromeric specificity, similar to the specificities within the voltage-dependent potassium channel superfamily. The second extracellular loop contains the primary determinants of the specificity of hemichannel-hemichannel docking (analogous to the tetramerization domain of potassium channels). The 7.5 A map shows that each monomer exposes only two transmembrane alpha-helices to the pore lumen. However the conductance state of the imaged structure and the effects of the C-terminal truncation are unknown, so it is possible that other transmembrane domains contribute to the lumen in other functional states of the channel. In the transmembrane region, SCAM and mutagenesis data suggest that parts of the first three transmembrane alpha-helices are exposed to the lumen. Some of these data are contradictory, but may reflect conformational or isoform differences. There is reason to think that the first part of the N-terminal cytoplasmic domain can line the pore in some conformations. In the extracellular part of junctional channels, the N-terminal portion of the first extracellular loop is exposed to the lumen. The unitary conductances through connexin channels vary over an order of magnitude, from 15 pS to over 300 pS. There is a range of charge selectivities among atomic ions, from slightly anion selective to highly cation selective, which does not correlate with unitary conductance. There appear to be substantial ion-ion interactions within the pore, making the GHK model of assessing selectivities of limited value. Pores formed by different connexins have a range of limiting diameters as assessed by uncharged and charged probes, which also does not correlate with unitary conductance (i.e. some have high conductance but have a narrow limiting diameter, and vice versa). Channels formed by different connexins have different permeabilities to various cytoplasmic molecules. Where it has been assessed, the selectivity among cytoplasmic molecules is substantial and does not correlate in an obvious manner with the size selectivity data derived from fluorescent tracer studies, suggesting there are chemical specificities within the pore that enhance or reduce permeability to specific cytoplasmic molecules, functionally analogous to the ability of some porins to facilitate transport of specific substrates. For example, heteromeric channels with different stoichiometries or arrangements of isoforms can distinguish among second messengers. The differences in permeability to cytoplasmic molecules have biological consequences; in most cases one connexin cannot fully substitute for another. Voltage and chemical gating mechanisms largely operate within each hemichannel, though there is evidence for inter-hemichannel allosteric effects as well. There are at least two distinct gating mechanisms. One (Vj-gating) is a voltage-driven mechanism that governs rapid transitions between conducting states. Its voltage sensor involves charges in the first several positions of the cytoplasmic N-terminal domain and possibly in the N-terminal part of the first extracellular loop, which may both be exposed to the lumen of the pore in some states. The polarity of Vj-gating sensitivity is connexin-specific, closing with depolarization for some connexins and with hyperpolarization for others. The polarity can be reversed by point mutations at the second position. The lower conductance states induced by Vj-gating correspond to physical restrictions of the pore, and thus restricted or eliminated molecular permeation. Since the channels are not fully closed by Vj-gating, it can be seen as a way to eliminate molecular signaling while leaving electrical signaling operational. A second, independent gating mechanism mediates slow transitions (approximately 10-30 ms) into and out of non-conducting state(s). These transitions can occur in response to voltage ('loop gating'), chemical factors such as pH and lipophiles ('chemical gating'), and the docking of two hemichannels (sometimes called the 'docking gate'). These slow transitions may reflect a common structural change induced by these several effectors (electrical, chemical and homodimerization). Alternatively, they could reflect distinct gating processes responding to one or more of these effectors, that are indistinguishable at the single-channel level and have yet to be resolved mechanistically. The slow or loop gate closes with hyperpolarization. As a result, where Vj-gating closes with depolarization, individual hemichannels can close in response to both polarities of voltage (but only to a subconductance state for the Vj-gating polarity). Because of this, it is difficult to assign a macroscopic voltage sensitivity, or its modification due to mutagenesis, chemical modification or heteromeric interactions, to one or the other of these very distinct voltage-sensitive processes. This distinction can be made reliably only at the single-channel level. The Vj-gating voltage sensor and the loop-gating voltage sensor appear to be independent structures, since the Vj-gating voltage sensitivity can modified without effect on loop gating. For some connexins, certain modifications of the C-terminal domain seem to interfere with the operation of the Vj-gate while leaving loop gating unaffected. In some connexins, but not all, the chemical sensitivity to pH can involve interactions between regions of the C-terminal domain and cytoplasmic loop. Whether these regions exert their effects directly by physically blocking the pore, or by allosteric mechanisms (which may be more consistent with the relatively long time-course of closure) is not clear. For several connexins, truncation of the C-terminal domain eliminates the pH sensitivity, and co-expressing the domain with the truncated connexin restores the pH sensitivity. This has a functional resemblance to the particle-receptor mechanism for N-type inactivation of Shaker channels. What is being protonated is not clear, and may involve cytoplasmic factors, such as endogenous aminosulfonates. For other connexins, the action of pH does not involve the C-terminal domain and seems due to direct protonation of connexin. PKC phosphorylation of serine(s) in the C-terminal domain can affect the substate occupancy of at least one connexin. Phosphorylation of series in the C-terminal domain by MAP kinase appears to facilitate an interaction between it and an unknown receptor domain to eliminate coupling. This process has yet to be studied at the single-channel level. It also has a functional analogy to the particle-receptor model of channel inactivation. Both MAP kinase phosphorylation-induced and pH-induced inhibition can be mediated in truncated connexins by the corresponding free peptide. However, the relation between these two mechanisms are unexplored, as are specific mechanisms of direct endogenous regulation of connexin channel activity. (ABSTRACT TRUNCATED)


Effect of abalone farming on seawater movement and benthic foraminiferal assemblage of Zostera marina in the inner bay of Wando, South Korea.
Tidal current survey as well as geochemical and benthic foraminiferal analyses of sediment cores were conducted in an abalone farm and a Zostera bed to understand the degree to which the abalone farm facilities installed along a channel in a shallow sea affect the benthic environment and ecology. In the abalone farm, Ammonia beccarii-Pseudoparrella naraensis-Elphidium somaense-Rosalina globularis-Trochammina hadai and P. naraensis-E. somaense-A. beccarii-T. hadai assemblages appeared owing to an increase in the total nitrogen content from the biodeposits. The Zostera bed consisted of A. beccarii-P. naraensis-Buccella frigida-T. hadai assemblage owing to the gradual expansion of a brackish shallow-water environment by the rapidly decreasing current speed, and it may have flourished. Moreover, the total sulfur, Zn, Cr, and Cu contents in the sediments decreased remarkably more than those of the pre-abalone farming did, caused by the vigorous activity of Zostera marina physiology.


Both atomoxetine and stimulants improve quality of life in an ADHD population treated in a community clinic.
To evaluate change in quality of life in a community clinic ADHD population treated with atomoxetine or stimulants. No direct comparisons between atomoxetine and stimulants to improve quality of life in ADHD are available. A prospective, nonrandomized comparison between ADHD patients treated with atomoxetine or stimulants in one clinic. Structured diagnostic assessment tools and a specific quality of life measure were used. 84 patients (atomoxetine n = 39/stimulants n = 45), between the ages of 5 and 18, were treated for approximately 8 months. At end point, there were no significant differences in improvements of quality of life between the two groups. Age, participation in psychotherapy, and parental disability were not correlated with quality of life changes. Patients with lower baseline scores improved most. Both atomoxetine and stimulants led to a modest increase in quality of life in this community clinic ADHD population.


Studies on hemopoietic chimerism following allogeneic bone marrow transplantation in the molecular biology era.
Donor hematopoiesis or donor chimerism in the host following allogeneic bone marrow transplantation (BMT) has appeared crucial to the engraftment process. However, as molecular techniques exploiting neutral variation in human genetic material have been used in the study of chimerism, the detection of residual host cells or mixed hemopoietic chimerism has indicated that donor chimerism is not obligatory following BMT. This review focuses on the detection and significance of mixed chimerism (MC) in patients transplanted for both malignant and non-malignant hemopoietic disease and attempts to tease out the contribution of MC to engraftment, leukemia relapse, graft rejection and long-term disease-free survival.


Structural MRI and Amyloid PET Imaging for Prediction of Conversion to Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Meta-Analysis.
The aim of this study was to explore the prognostic values of biomarkers of neurodegeneration as measured by magnetic resonance imaging (MRI) and amyloid burden as measured by amyloid positron emission tomography (PET) in predicting conversion to Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). PubMed and EMBASE databases were searched for structural MRI or amyloid PET imaging studies published between January 2000 and July 2014 that reported conversion to AD in patients with MCI. Means and standard deviations or individual numbers of biomarkers with positive or negative status at baseline and corresponding numbers of patients who had progressed to AD at follow-up were retrieved from each study. The effect size of each biomarker was expressed as Hedges's g. Twenty-four MRI studies and 8 amyloid PET imaging studies were retrieved. 674 of the 1741 participants (39%) developed AD. The effect size for predicting conversion to AD was 0.770 [95% confidence interval (CI) 0.607-0.934] for across MRI and 1.316 (95% CI 0.920-1.412) for amyloid PET imaging (p<0.001). The effect size was 1.256 (95% CI 0.902-1.609) for entorhinal cortex volume from MRI. Our study suggests that volumetric MRI measurement may be useful for the early detection of AD.


Teratological evaluation of the phenoxyacid herbicide MCPA in the regenerating forelimb of the adult newt.
The effects of a commercial formulation of the phenoxyacid herbicide 2-methyl-4-chlorophenoxyacetic acid sodium salt (MCPA) on the regenerating forelimb of the adult crested newt were studied. The animals were exposed percutaneously to 0, 200, 400, or 800 ppm of MCPA for 4 days a week throughout the regeneration period and were sacrificed 11 weeks after amputation. The concentrations tested did not cause histologically detectable toxic lesions of the examined organs. Exposure to MCPA resulted in a significant retardation of the morphogenetic process as evidenced by skeletal examination. At the highest concentration tested, a significant growth delay was also evident during the regeneration period. No significant differences in the frequency of skeletal malformations were observed between control and treated newts, although the frequency was higher in the latter.


[Endonasal microscopic surgery of the lacrimal duct stenosis--long-term results].
The value of a complex endonasal microsurgical treatment of lacrimal duct stenosis. in a group of 418 patients we performed 455 dacryocystorhinostomy (DCR) including 37 bilaterally. They were 263 females (62.9%) and 155 males (37.1%). Age ranged from 1.5 to 87, mean age 54.3 years. Performance: general anaesthesia with controlled hypothension, semi sitting position of patient and adjustable headrest, operating microscope (300 mm lens). Operative procedure: septum mobilization and anterior ethmoidectomy, dacryocystorhinostomy (DCR). satisfactory results were obtained in 436 of cases (95.8%), 19 no change (4.2%). Only 18 cases received a prosthesis. There were only 2 complications (0.2) not serious. endonasal microscopic dacryocystorhinostomy preserves intact bony support and frame of lacrimal ducts and the nasal function of the lacrimal pump. It allows simultaneous management of the concomitant sino-nasal pathology as well as shorter operation times, lower complication rates and reduced patient morbidity.


Shaping the Treatment Paradigm Based on the Current Understanding of the Pathobiology of Multiple Myeloma: An Overview.
Multiple myeloma is an incurable malignancy which despite progressive improvements in overall survival over the last decade remains characterised by recurrent relapse with progressively shorter duration of response and treatment-free intervals with each subsequent treatment. Efforts to unravel the complex and heterogeneous genomic alterations, the marked dysregulation of the immune system and the multifarious interplay between malignant plasma cells and those of the tumour microenvironment have not only led to improved understanding of myelomagenesis and disease progression but have facilitated the rapid development of novel therapeutics including immunotherapies and small molecules bringing us a step closer to therapies that no doubt will extend survival. Novel therapeutic combinations both in the upfront and relapsed setting as well as novel methods to assess response and guide management are rapidly transforming the management of myeloma.


Female-male mounting in Japanese macaques: the proximate role of sexual reward.
Female Japanese macaques (Macaca fuscata), in certain populations, routinely engage in female-male mounting. In this study, we documented patterns of vulvar, perineal and anal (VPA) stimulation during female-male mounting in Japanese macaques. During approximately 45% of the female-male mounts analyzed, two thirds of female mounters engaged in VPA stimulation. Given the VPA region's primary role in mediating sexual response, the results of this research provide direct evidence bearing on the sexual nature of a substantial proportion of female-male mounts in Japanese macaques.


An Educational Experiment Resulting from COVID-19: The Use of At-Home Waxing and Webinars for Teaching a 3-Week Intensive Course in Tooth Morphology to First Year Dental Students.
To report the outcomes of presenting a 3-week intensive course in tooth morphology to first year dental students using "at-home" waxing projects and webinars. Students were provided with the instrumentation and materials required to complete 5 waxing projects at home during the 3-week course. In the same time period, the didactic content was presented via 11 webinar sessions. A postcourse survey provided student perspectives regarding this new experience. Students were able to effectively complete high-quality waxing projects at home by using step-by-step images and videos but the survey indicated an overwhelming preference for in-person faculty feedback. Webinars based on the students having studied the 3D Tooth Atlas and an instructor reviewing content in the Atlas was effective in teaching the didactic aspect of tooth morphology as evidenced by the student grades and survey results. However, most of the students indicated a preference for physically going to class and being able to interact with faculty and classmates as opposed to online webinars. The condensed 3-week version of the course was part of an expanded 4-week student orientation and worked well, allowing other clinical precursor courses to occur before their usual time in the curriculum, thereby allowing students to begin earlier patient treatment. The at-home waxing exercises produced very good results by having the students use step-by-step images and videos in the 3D Tooth Atlas. However, the students indicated a strong preference for personal faculty feedback that was not available at home. Students effectively learned the didactic aspects of tooth morphology through the webinars with accompanying use of the 3D Tooth Atlas but again most students prefer physically going to class and being able to interact with faculty and classmates. These preferences for contact with classmates and faculty supports the natural human desire for personal interactions with other human beings.


Ecological significance of alkaline phosphatase activity and phosphatase-hydrolyzed phosphorus in the northern part of Gamak Bay, Korea.
We investigated the ecological significance of alkaline phsophatase (APase) and alkaline phosphatase-hydrolyzable phosphorus (APHP) in the northern part of Gamak Bay, Korea. APase activity was detectable throughout the year, and dissolved inorganic phosphorus (DIP) concentration and APase activity are highly correlated and can be regarded as an indicator of DIP-limiting conditions. Also, a strong linear positive correlation between APase activity and Chl a concentration indicated that the major part of APase activity may have been induced by phytoplanktons. The APHP proportion in dissolved organic phosphorus (DOP) was above ca. 30% from winter to spring and below ca. 15% from summer to autumn due to freshwater discharge and uptake by phytoplankton. APHP may play an important role in species competition in coastal area such as northern part of Gamak Bay where DIP is limiting. Thus, APase induction by phytoplanktons may be ecologically significant, allowing dominance by these organisms under DIP-limiting conditions.


[Endovascular Treatment for Head and Neck Trauma].
Trauma to the head and neck region can have serious consequences for vital organs such as the brain, and injuries to blood vessels can cause permanent neurological damage or even death. Thus, prompt treatment of head and neck vessels is crucial. Although the level of evidence is moderate, an increasing amount of research indicates that endovascular treatments can be a viable alternative to traditional surgery or medical management. Embolization or reconstructive endovascular procedures can significantly improve patient outcomes. This article provides an overview of various endovascular options available for specific clinical scenarios, along with examples of cases in which they were employed.


Variations in DNA methylation patterns during the cell cycle of HeLa cells.
DNA methylation has been viewed as a stable component of the epigenome, established during development and fixed thereafter. Here we have found that the DNA methylation pattern varies during a single cell cycle, with the global levels of DNA methylation decreased in G(1) and increase during S phase. There was little change in the DNA methylation levels in repetitive sequences throughout the cell cycle. However using a human CpG island microarray it was revealed that 174 CG-containing sequences were differentially methylated between G(1) and S. Seventy-five percent of all the variations in DNA methylation detected in unique sequences represented hypomethylation at G(0), with changes occurring in both CpG islands and non-CpG islands. This is the first demonstration of a dynamic DNA methylation pattern within a single cell cycle of a mature somatic cell. These data are important for our understanding of the stability of DNA methylation patterns in somatic cells.


Early weaning effects on voluntary ethanol consumption and stress responsivity in rats.
The present study examined the effect of early maternal deprivation (early weaning) on voluntary ethanol consumption and responses to cold-immobilization stress in adult rats. Rats were weaned at 16 and 21 days of age and housed individually with food and water ad lib until they reached 190 +/- 5 g at which time half of the animals from each group were exposed to increasing concentrations (3 to 9%) of ethanol in a free choice with water every alternate day. Following acquisition of ethanol drinking, animals were provided with water and ethanol (9%) daily for eight days. At the end of this period, animals were divided into stressed and non-stressed groups. Stressed animals were exposed to cold immobilization stress for 3 hr. Results showed that the early-weaned animals consumed significantly more ethanol as compared to normal-weaned animals. Stomach pathology data revealed little ulcer formation in water-only groups. However, normal-weaned/ethanol-exposed animals exhibited significantly more severe ulcers when compared to all other water- or ethanol-exposed groups. We suggest that early maternal deprivation may predispose animals to increased ethanol consumption as adults. Stress ulcer susceptibility in these animals was likely influenced by interactions among the effects of early weaning, ethanol intake and handling and needs further clarification.


Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers.
Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care. From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model. Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics. Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.


Panakeia - a universal tool for bacterial pangenome analysis.
Development of new pan-genome analysis tools is important, as the pangenome of a microbial species has become an important method to define the diversity of a selected taxon, most commonly a species, in the last years. This enables comparison of strains from different ecological niches and can be used to define the functional potential in a bacterial population. It gives us a much better view of microbial genomics than can be gained from singular genomes which after all are just single representatives of a much more varied population. We present Panakeia, a tool which strives to be easy to use and providing a detailed view of the pangenome structure which can efficiently be utilised for discovery, or further in-depth analysis, of features of interest. It analyses synteny and multiple structural patterns of the pangenome, giving insights into the biological diversity and evolution of the studied taxon. Panakeia hence provides both broad and detailed information on the structure of a pangenome, for diverse and highly clonal populations of bacteria. Previously published pangenome tools often reduce the information to a presence/absence matrix of unconnected genes or generate massive hard to interpret output graphs. However, Panakeia includes synteny and structural information and presents it in a way that can readily be used for further analysis. Panakeia can be downloaded at https://github.com/BioSina/Panakeia together with a detailed User Guide.


Medication prescribing errors in the medical intensive care unit of Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia.
Medication errors (MEs) are important problems in all hospitalized populations, especially in intensive care unit (ICU). Little is known about the prevalence of medication prescribing errors in the ICU of hospitals in Ethiopia. The aim of this study was to assess medication prescribing errors in the ICU of Tikur Anbessa Specialized Hospital using retrospective cross-sectional analysis of patient cards and medication charts. About 220 patient charts were reviewed with a total of 1311 patient-days, and 882 prescription episodes. 359 MEs were detected; with prevalence of 40 per 100 orders. Common prescribing errors were omission errors 154 (42.89%), 101 (28.13%) wrong combination, 48 (13.37%) wrong abbreviation, 30 (8.36%) wrong dose, wrong frequency 18 (5.01%) and wrong indications 8 (2.23%). The present study shows that medication errors are common in medical ICU of Tikur Anbessa Specialized Hospital. These results suggest future targets of prevention strategies to reduce the rate of medication error.


Can wrist blood pressure oscillometer be used for triage in an adult emergency department?
We compare the performance of a wrist blood pressure oscillometer with the mercury standard in the triage process of an emergency department (ED) and evaluate the impact of wrist blood pressure measurement on triage decision. Blood pressure was successively measured with the standard mercury sphygmomanometer and with the OMRON-RX-I wrist oscillometer in a convenience sample of 2,493 adult patients presenting to the ED with non-life-threatening emergencies. Wrist and mercury measures were compared using criteria of the Association for the Advancement of Medical Instrumentation (AAMI) and the British Hypertension Society (BHS). The impact on triage decisions was evaluated by estimating the rate of changes in triage decisions attributable to blood pressure results obtained with the wrist device. Wrist oscillometer failed to meet the minimal requirements for recommendation by underestimating diastolic and systolic blood pressure. Mean (+/-SD) differences between mercury and wrist devices were 8.0 mm Hg (+/-14.7) for systolic and 4.2 mm Hg (+/-12.0) for diastolic measures. The cumulative percentage of blood pressure readings within 5, 10, and 15 mm Hg of the mercury standard was 32%, 58%, and 72% for systolic, and 40%, 67%, and 83% for diastolic measures, respectively. Using the wrist device would have erroneously influenced the triage decision in 7.6% of the situations. The acuity level would have been overestimated in 2.2% and underestimated in 5.4% of the triage situations. The performance of the OMRON-RX-I wrist oscillometer does not fulfill the minimum criteria of AAMI and BHS compared with mercury standard in the ED triage setting.


Nanoextraction Coupled to Liquid Chromatography Mass Spectrometry Delivers Improved Spatially Resolved Analysis.
Direct analyte-probed nanoextraction (DAPNe) is a technique that allows extraction of drug and endogenous compounds from a discrete location on a tissue sample using a nano capillary filled with solvent. Samples can be extracted from spot diameters as low as 6 μm. Studies previously undertaken by our group have shown that the technique can provide good precision (5%) for analyzing drug molecules in 150 μm diameter areas of homogenized tissue, provided an internal standard is sprayed on to the tissue prior to analysis. However, without an isotopically labeled standard, the repeatability is poor, even after normalization to the spot area or matrix compounds. By application to tissue homogenates spiked with drug compounds, we can demonstrate that it is possible to significantly improve the repeatability of the technique by incorporating a liquid chromatography separation step. Liquid chromatography is a technique for separating compounds prior to mass spectrometry (LC-MS) which enables separation of isomeric compounds that cannot be discriminated using mass spectrometry alone, as well as reducing matrix interferences. Conventionally, LC-MS is carried out on bulk or homogenized samples, which means analysis is essentially an average of the sample and does not take into account discrete areas. This work opens a new opportunity for spatially resolved liquid chromatography mass spectrometry with precision better than 20%.


Pre-operative staging of breast cancer with breast MRI: one step forward, two steps back?
In the field of oncologic surgery, an accurate local staging, i.e. the delineation of local disease extent, is considered of key importance to guide treatment decisions in patients with operable cancers, in particular patients who are operated on with curative intention. Imaging studies are used to provide a road map for the surgeon to help him or her obtain clear margins-which, in turn, is considered essential in order to avoid recurrent disease. It is well established that breast MRI is by far superior to mammography, with or without concomitant ultrasound, for the local staging of breast cancer. MRI allows the most accurate delineation of the size and the local extent of cancer, including the depiction of multifocal or multicentric or contralateral disease. MRI offers the highest sensitivity for demonstrating intraductal extensions around invasive cancers. Due to its very high negative predictive value, MRI can be used to confidently exclude the presence of breast cancer, and, thus, avoid unnecessary surgery. For all these reasons, MRI should be considered an integral part of the work up of patients who undergo breast-conserving treatment for breast cancer. And yet, the technique is only slowly adopted in clinical practice. Arguments against the use of breast MRI include costs, frequency of false positive diagnoses, lack of availability of minimally invasive biopsy capabilities, lack of evidence by randomized controlled clinical trials, and, last, fear of overtreatment. In this article, these concerns are explained, discussed and weighted against the advantages of pre-operative breast MRI for breast cancer staging. The point is made that breast MRI is essential for surgical planning, but that indeed unnecessary mastectomy may result if old guidelines are simply copied onto a new situation. Guidelines that require mastectomy for multicentric breast cancer have been established before the advent of MRI. Using the same guidelines to manage MR-detected multicentric cancer foci may be inappropriate because some small MRI detected additional multicentric breast cancer foci will be sufficiently treated by radiation therapy.


Antibodies to the neuronal cytoskeleton are elicited by Alzheimer paired helical filament fractions.
Antibodies were raised to paired helical filament (PHF) enriched fractions obtained from brains of individuals with Alzheimer disease by extraction with ionic detergent followed by sucrose gradient centrifugation. Electron microscopic examination showed that the fractions were enriched in Alzheimer PHF but contained also lipofuscin, amyloid, granular material and membranous elements. Analysis of these fractions with SDS-PAGE stained with Coomassie blue showed only a faint band at approximately 60 kDa while most of the material was excluded from the stacking gel. BALB/c mice were injected weekly with 100 or 200 micrograms of these fractions or corresponding fractions from age-matched control brains. The 3 mice injected with Alzheimer brain, but not the 5 mice injected with control brain fractions, produced antibodies that reacted with central and peripheral nervous system axons, Alzheimer neurofibrillary tangles in intact tissue as well as with isolated, SDS-treated paired helical filaments. In gel strips antibodies from all 3 mice injected with Alzheimer brain fractions reacted with the 200-kDa and 168-kDa but not the 68-kDa neurofilament subunits. The 3 antisera reacted also with some forms of the microtubule-associated protein tau. Adsorptions with the insoluble fraction from Alzheimer but not from control brains blocked staining of axons and NFT by all 3 antisera. Adsorption with highly purified neurofilament proteins or with a preparation containing the 200-kDa and 168-kDa neurofilament subunits blocked axon and NFT immunostaining only in one antiserum. Adsorptions with microtubule protein, heat-stable microtubule-associated protein, or a preparation of tau did not completely block immunostaining by any of the 3 antisera. These results demonstrate that fractions enriched with Alzheimer paired helical filaments contain insoluble neurofilament, tau and other yet unidentified antigens.


Association between triglyceride glucose index and risk of cerebrovascular disease: systematic review and meta-analysis.
The triglyceride glucose (TyG) index, which is a new surrogate indicator of insulin resistance (IR), is thought to be associated with many diseases, such as cardiovascular disease, but its relationship with cerebrovascular disease is still controversial. The PubMed, EMBASE, Cochrane Library, Web of Science and Medline databases were searched until March 2022 to evaluate the association between the TyG index and cerebrovascular disease risk. A random‒effects model was used to calculate the effect estimates and 95% confidence intervals (CIs). A total of 19 cohort studies and 10 case‒control/cross‒sectional studies were included in our study, which included 11,944,688 participants. Compared with a low TyG index, a higher TyG index increased the risk of cerebrovascular disease (RR/HR = 1.22, 95% CI [1.14, 1.30], P< 0.001; OR = 1.15, 95% CI [1.07, 1.23], P< 0.001). Furthermore, the results of the dose-response analysis of the cohort study demonstrated that the risk of cerebrovascular disease increased by 1.19 times per 1 mg/dl increment of the TyG index (relative risk = 1.19, 95% CI [1.13,1.25], P< 0.001). TyG index is related to cerebrovascular disease. More data and basic research are needed to confirm the association.


In vitro studies on IgG-mediated lymphocyte cytotoxicity in chronic active liver disease.
Antibody-dependent cytotoxicity in chronic active liver disease (CALD) (10 subjects), mediated by allogeneic nonimmune lymphocytes (NL), was studied in vitro. NL in significant numbers adhered to the surface of target Chang monolayer cells, pretreated with the sera of CALD patients (immune adherence of NL) and were cytotoxic. This was blocked by anti-IgG and IgGFc. Test sera, absorbed with Chang cells or human adult liver tissues, failed to provoke target Chang cell lysis. Small amounts of granular-appearing IgG were demonstrated on the surface of Chang cells treated with the CALD sera from 8 of the 10 patients (membrane-fixed IgG). It is concluded that the antibody-dependent cellular cytotoxicity in this in vitro system is mediated by the IgG of CALD sera, most likely bound to target cell surface antigens, and that effector NL appear to lyse the target cells by direct contact through the Fc portion of the above membrane-fixed IgG. This immune cytotoxic process may play a role in the pathogenesis of CALD.


Inhibitory effects of triamcinolone acetonide on bFGF-induced migration and tube formation in choroidal microvascular endothelial cells.
Angiostatic drugs might provide desirable modulation of choroidal angiogenesis-related diseases, including histoplasmosis and the exudative form of age-related macular degeneration. However, the precise effects of this class of compounds in the choroidal neovascularization are still unclear. In the present study, we investigated the effects of triamcinolone acetonide (TA), an angiostatic steroid, on choroidal angiogenesis in vitro. Bovine choroidal endothelial cells (CEC), which are the critical cellular component of choroidal angiogenesis in vivo, were isolated with Lycopersicon esculentum agglutinin-coated Dynabeads and cultured in EGM medium. CEC were treated with basic fibroblast growth factor (bFGF) and TA at various concentrations ranging from 50 to 300 mg/l. The capacities for CEC migration and tube formation were evaluated with the modified Boyden chamber and the Vitrogen collagen assay, respectively. The activities of matrix metalloproteinases (MMP)-2 and -9 were examined using gelatin zymography. The stimulation of CEC with 50 ng/ml bFGF resulted in an increase of about 100% in migration activity (P<0.01). Preincubation of CEC with TA at the indicated concentrations for 20 min inhibited the bFGF-stimulated migration in a dose-dependent manner (P<0.01). After 5 days, the bFGF-stimulated tube formation in CEC was inhibited by TA at the concentrations 100, 150 and 300 mg/l (P<0.01). Gelatin zymography of the culture media of CEC showed that the bFGF-induced activation of MMP-2 was attenuated by 300 mg/l TA (P<0.05). Downregulation of the activation of MMPs in CEC could be one of the mechanisms by which angiostatic steroids inhibit choroidal angiogenesis.


Altered zinc status of soldiers under field conditions.
Thirty men were studied during a 34-day intensive training exercise conducted by the U.S. Army. All soldiers were followed to determine the effect of such training, designed to simulate wartime operations, on selected zinc parameters. The soldiers consumed a nutritionally adequate diet made from fresh foods (A rations) prepared at the training site. Dietary intake, weight change, serum zinc, alkaline phosphatase activity, and urinary zinc excretion were measured. The 34-day intensive training exercise was associated with weight loss, depressed serum zinc levels, and elevated urinary zinc excretion. Alkaline phosphatase activity was not altered by the training exercise. The depressed serum zinc concentration could not be explained by the parameters measured. Weight loss was positively correlated with urinary zinc excretion. The functional significance of a depressed serum zinc concentration on performance deserves further study.


A simple method of estimating the size of large pituitary adenomas.
A method of measuring the volume of large pituitary adenomas is described. Measurements obtained are useful in the follow-up of patients whose tumours are treated by partial excision and radiotherapy. The method is felt also to be useful in judging whether or not a tumour should be designated a giant one thereby aiding management as well as follow-up. The method is simple and easily repeatable.


Hetero Bodipy-dimers as heavy atom-free triplet photosensitizers showing a long-lived triplet excited state for triplet-triplet annihilation upconversion.
Bodipy dimers in which the two different sub-units take an orthogonal orientation were prepared, which show strong absorption of visible light, long-lived triplet excited states (140.9 μs) and high singlet oxygen ((1)O2) quantum yields (64%). The dimers were used for triplet-triplet annihilation upconversion (quantum yield is up to 3.7%).


DIALIGN at GOBICS--multiple sequence alignment using various sources of external information.
DIALIGN is an established tool for multiple sequence alignment that is particularly useful to detect local homologies in sequences with low overall similarity. In recent years, various versions of the program have been developed, some of which are fully automated, whereas others are able to accept user-specified external information. In this article, we review some versions of the program that are available through 'Göttingen Bioinformatics Compute Server'. In addition to previously described implementations, we present a new release of DIALIGN called 'DIALIGN-PFAM', which uses hits to the PFAM database for improved protein alignment. Our software is available through http://dialign.gobics.de/.


LINC00473 rescues human bone marrow mesenchymal stem cells from apoptosis induced by dexamethasone through the PEBP1‑mediated Akt/Bad/Bcl‑2 signaling pathway.
The inhibition of the proliferation and apoptosis of bone marrow‑derived mesenchymal stem cells (BMSCs) triggered by the excessive use of glucocorticoids, is considered a potential mechanism for the pathogenesis of steroid‑induced osteonecrosis of the femoral head (SONFH). Long non‑coding RNAs (lncRNAs) have been proven to influence the proliferation, apoptosis and differentiation of BMSCs by regulating the expression of critical genes. A previous microarray analysis by the authors confirmed the significant downregulation of LINC00473 in human BMSCs (hBMSCs) from patients with SONFH. However, the underlying role and molecular mechanisms of LINC00473 on dexamethasone (Dex)‑stimulated hBMSCs remains unknown. In the present study, the expression of LINC00473 was determined in the hBMSCs of patients with SONFH and control patients. In addition, the protective effects and underlying molecular mechanisms of LINC00473 in Dex‑stimulated hBMSCs were investigated. The results revealed that LINC00473 expression was significantly downregulated in hBMSCs from patients with SONFH compared with the controls, and that the upregulation of LINC00473 attenuated the inhibitory effects exerted by 1 µM Dex on the proliferation and apoptosis of hBMSCs. Moreover, the upregulation of LINC00473 significantly promoted the protein expression of phosphorylated (p‑)Akt, p‑Bcl‑2‑associated death promoter (p‑Bad) and B‑cell lymphoma 2 (Bcl‑2), whereas it decreased the cleavage of caspase‑3, thus preventing the Dex‑induced apoptosis of hBMSCs. Of note, the regulatory effects of LINC00473 on the Akt/Bad/Bcl‑2 signaling pathway and its anti‑apoptotic effects were similar to those of SC79 (an Akt activator), and were inhibited by MK‑2206 (an Akt inhibitor). In further experiments, it was found that the upregulation of LINC00473 markedly promoted the phosphorylation of Akt in Dex‑stimulated hBMSCs, and increased the protein level of phosphatidylethanolamine‑binding protein 1 (PEBP1). Alternatively, the promoting effect on Akt phosphorylation induced by LINC00473 was significantly attenuated following the knockdown of PEBP1. Furthermore, the upregulation of PEBP1 triggered a marked increase in the levels of Akt phosphorylation in Dex‑stimulated hBMSCs, which was line with the upregulation of LINC00473. Taken together, the results of the present study demonstrate that LINC00473 has the ability to rescue hBMSCs from Dex‑induced apoptosis through the PEBP1‑mediated activation of the Akt/Bad/Bcl‑2 signaling pathway.


Genomic approaches to study genetic and environmental influences on fish sex determination and differentiation.
The embryonic gonad is the only organ that takes two mutually exclusive differentiating pathways and hence gives rise to two different adult organs: testes or ovaries. The recent application of genomic tools including microarrays, next-generation sequencing approaches, and epigenetics can significantly contribute to decipher the molecular mechanisms involved in the processes of sex determination and sex differentiation. However, in fish, these studies are complicated by the fact that these processes depend, perhaps to a larger extent when compared to other vertebrates, on the interplay of genetic and environmental influences. Here, we review the advances made so far, taking into account different experimental approaches, and illustrate some technical complications deriving from the fact that as development progresses it becomes more and more difficult to distinguish whether changes in gene expression or DNA methylation patterns are the cause or the consequence of such developmental events. Finally, we suggest some avenues for further research in both model fish species and fish species facing specific problems within an aquaculture context.


Results of Heller's operation for achalasia of the cardia.
A survey of 102 patients with achalasia of the cardia treated by cardiomyotomy is reported. The technique of operation was unchanged throughout and the patients were followed up for a maximum of 22 years. Only 6 patients (5.8 per cent) developed renewed symptoms of reflux and 7 patients (6.8 per cent) had peptic strictures. Over 80 per cent of the patients had no dysphagia or regurgitation postoperatively, but 61 per cent still complained of achalasic pain. The development of mucosal hernias after cardiomyotomy and the use of drinking times in the assessment of outflow at the cardia are discussed.


De novo gastrointestinal tumours after renal transplantation: role of CMV and EBV viruses.
The development of new and more effective immunosuppressive agents has provided long-term survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic immunocompromised hosts. While de novo post-transplant lymphoproliferative diseases and skin cancer has been shown to have an increased incidence in long-term surviving solid organ transplant recipients, the association with gastrointestinal (GI) cancer is controversial. Over 12 yr, 20 patients (5%) out of 395 renal transplant recipients developed 23 de novo tumours; 11 skin cancer and 12 non-skin cancer. Four patients (1%) developed de novo tumours of the GI tract (three colon, and one gastric cancer). Immediately after tumour's diagnosis, immunosuppressive therapy was reduced; all patients were shifted from cyclosporine to Rapamicine within 30 d. The tumour was surgically resected with curative intent in three cases, while one patient had only palliative surgery because of metastatic disease. The post-operative courses was uneventful. All patients maintained normal graft function. However, three out of four patients (75%) died of progression of the neoplasm, within a median time from the diagnosis of 12 months. Further, we investigated a possible correlations between de novo GI cancer and HCV, HBV status, infections, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation, episodes of rejection, and blood transfusions. All cases with GI de novo cancers reported in this paper developed CMV and EBV reactivation within three months after transplantation. Thereafter we suggest a closer follow-up for de novo GI cancer in renal transplants with early CMV and EBV reactivation in order to avoid delayed diagnosis.


Optimal Frequency of Urinary Albumin Screening in Type 1 Diabetes.
Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We aimed to determine a simple, risk factor-based screening schedule that optimizes early detection and testing frequency. Urinary albumin excretion measurements from 1,343 participants in the Diabetes Control and Complications Trial and its long-term follow-up were used to create piecewise-exponential incidence models assuming 6-month constant hazards. Likelihood of the onset of moderately or severely elevated albuminuria (confirmed albumin excretion rate AER ≥30 or ≥300 mg/24 h, respectively) and its risk factors were used to identify individualized screening schedules. Time with undetected albuminuria and number of tests were compared with annual screening. The 3-year cumulative incidence of elevated albuminuria following normoalbuminuria at any time during the study was 3.2%, which was strongly associated with higher glycated hemoglobin (HbA1c) and AER. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8% (low risk [0.6% three-year cumulative incidence]), in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9% (high risk [8.9% three-year cumulative incidence]), and in 1 year for all others (average risk [2.4% three-year cumulative incidence]) was associated with 34.9% reduction in time with undetected albuminuria and 20.4% reduction in testing frequency as compared with annual screening. Stratification by categories of HbA1c or AER alone was associated with reductions of lesser magnitude. A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing. Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We investigated simple screening schedules that optimize early detection and testing frequency. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8%, in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9%, and in 1 year for all others yielded 34.9% reduction in time with undetected albuminuria and 20.4% fewer evaluations compared with annual screening. A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing.


A prospective, open, randomized clinical study to assess the efficacy and safety of two gonadotropin preparations administered in WHO Group II anovulatory subfertile women.
To assess the efficacy and safety of 2 gonadotropin preparations in inducing ovulation in clomiphene-resistant WHO Group II anovulatory subfertile women. Twenty-patients were randomized to receive either Metrodin intramuscularly or Metrodin HP subcutaneously and underwent 45 treatment cycles. A maximum of 3 cycles were offered unless conception or severe adverse reaction occurred. The presence of redness, swelling, bruising and pain of the injection sites was noted and compared. Seven patients became pregnant (3 in the Metrodin group and 4 in the Metrodin HP group) and the pregnancy rates per patient and per cycle were 7/20 (35%) and 7/45 (15.6%), respectively. No local reactions were found in the majority of cycles. There was no significant difference in pregnancy rates and the number of cycles complicated by bruise, pain, itching, redness or swelling between these 2 groups. This clinical study shows that in WHO Group II anovulatory patients Metrodin HP administered subcutaneously by self-injection is as safe and effective as Metrodin administered intramuscularly in inducing ovulation.


Biosimilars in Malaysia: Regulatory Framework, Approved Products, and Adverse Effects.
Biosimilars are a cost-effective alternative to original biologic medicines that allow patients access to biologic therapies for various chronic diseases. Our paper aims to provide an overview of biosimilars in Malaysia with emphasis on the comparison of Malaysian guidelines with guidelines from well-established regulatory agencies, a review of biosimilars' market approval and their reported adverse effects (AEs) as well as clinical trials conducted in Malaysia. We searched the official websites of the National Pharmaceutical Regulatory Agency (NPRA) Malaysia and three other well-established agencies, online databases of Medline® and EMBASE for guidelines on legislation and regulations of biosimilars. Meanwhile, we extracted the reports of AEs involving biosimilars in Malaysia from the NPRA database and for global AEs from the World Health Organisation VigyLize database. The ClinicalTrials.gov Website by the U.S. National Library of Medicines was the source for data on clinical trials. Malaysia followed the principles of the European Medicines Agency biosimilar regulations and issued their guideline in 2008. Since then, NPRA has approved 24 biosimilar products and recorded 499 AE reports, of which 43 (8.6%) were serious. NPRA has also approved ten Phase III clinical trials in Malaysia with four trials still ongoing. Malaysia follows a stringent regulatory pathway for the approval of biosimilars enacted by well-established regulatory agencies to maintain the quality, efficacy and safety of biosimilars. Introducing biosimilars to the Malaysian market would improve patients' accessibility to biologic therapies.


[The detection of human DNA in cell hybrids by the polymerase chain reaction with universal primers: the species specificity of the amplified DNA].
The human DNA detection method is developed on the basis of DNA cross-hydridization of the amplification products obtained by the universally primed polymerase chain reaction (UP-PCR) technique. These PCR products are characterized by species-specificity in hybridization assay. Two somatic cell hybrids "human x Chinese hamster" supposed to contain the human DNA, according to selection procedure, were analysed by this method. As a result, the presence of human DNA, unable to be tested by cytological techniques, have been proven. The amplified human DNA can be mapped by this method.


Calreticulin expression levels and endoplasmic reticulum during late oogenesis and early embryogenesis of Rhodnius prolixus Stahl.
This study reports the cloning, expression analysis and localization of calreticulin (CRT) in the endoplasmic reticulum (ER) during late oogenesis and early embryogenesis of the insect Rhodnius prolixus. CRT was cloned and sequenced from cDNA extracted from unfertilized eggs. Real-time PCR showed that CRT expression remains at lower levels during late oogenesis when compared to vitellogenic oocytes or day 0 laid fertilized eggs. Immunofluorescence microscopy showed that this protein is located in the periphery of the egg, in a differential peripheral ooplasm surrounding the yolk-rich internal ooplasm, only identified by transmission electron microscopy (TEM) of thin sections. Using immunogold electron microscopy, the ER ultrastructure (CRT labeled) was identified in the peripheral ooplasm as dispersed lamellae, randomly distributed in the peripheral ooplasm. No massive alterations of ER ultrastructure were found before or right after (30 min) fertilization, but an increase in CRT expression levels and assembly of typical rough ER (parallel cisternae with associated ribosomes) were observed 18-24 h after oviposition. The lack of ER assembly at fertilization and the later formation of rough ER together with the increase in CRT expression levels, suggest that the major functions of ER might be of great importance during the early events of development. The possible involvement of ER in the early steps of embryogenesis will be discussed.