Brain Microstructural Correlates of Cognitive Dysfunction in Clinically and Biochemically Normal Hepatitis C Virus Infection.
This study examined correlates of the brain's neurocognitive performance among clinically and biochemically normal adult patient with hepatitis C virus (HCV). We hypothesized that anti-HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using diffusion tensor tractrography (DTT) metrics. Anti-HCV positive patient (n = 40), and healthy controls (n = 31), fulfilling inclusion criteria (incidentally detected anti-HCV positive) and able to provide informed consent were screened and recruited for the study. All these subjects and controls underwent subjective assessment of their quality of life related symptoms, neuropsychometric tests (NPT) and magnetic resonance imaging. The patients were subjected to neuroimaging as well as psychological testing. There was no significant difference in basic laboratory parameters in these two groups. Independent t-test reveals significantly lower neuropsychological functioning as compared to healthy control. A significantly decreased FA values and myoinsitol were observed in HCV subjects on sensory, inferior longitudinal fascicules, and STR fiber bundles as compared to healthy control. Bivariate correlation analysis reveals that neuropsychological scores are significantly positive. Our result show that HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using DTT metrics.


A novel noise filtered and occlusion removal: navigational accuracy in augmented reality-based constructive jaw surgery.
Augmented reality-based constructive jaw surgery has been facing various limitations such as noise in real-time images, the navigational error of implants and jaw, image overlay error, and occlusion handling which have limited the implementation of augmented reality (AR) in corrective jaw surgery. This research aimed to improve the navigational accuracy, through noise and occlusion removal, during positioning of an implant in relation to the jaw bone to be cut or drilled. The proposed system consists of a weighting-based de-noising filter and depth mapping-based occlusion removal for removing any occluded object such as surgical tools, the surgeon's body parts, and blood. The maxillary (upper jaw) and mandibular (lower jaw) jaw bone sample results show that the proposed method can achieve the image overlay error (video accuracy) of 0.23~0.35 mm and processing time of 8-12 frames per second compared to 0.35~0.45 mm and 6-11 frames per second by the existing best system. The proposed system concentrates on removing the noise from the real-time video frame and the occlusion. Thus, the acceptable range of accuracy and the processing time are provided by this study for surgeons for carrying out a smooth surgical flow.


Impact of serum insulin-like growth factor-1 on early prognosis in acute myocardial infarction.
Previous research revealed that a low concentration of serum insulin-like growth factor-1 (IGF-1) is associated with risks of myocardial infarction and heart failure. We hypothesized that the serum IGF-1 level affects clinical outcome in acute myocardial infarction (AMI). We examined the impact of serum IGF-1 in acute phase of AMI on 90-day mortality. In 54 patients with AMI, we measured serum total IGF-1 concentration on admission, in acute phase (1.9+/-0.5 days) and in chronic phase (28.5+/-6.7 days). We measured plasma brain natriuretic peptide (BNP), glucose and insulin in acute phase, and calculated insulin resistance (HOMA-R). Serum IGF-1 was 135.6+/-51.1 ng/ml on admission and significantly decreased to 105.5+/-42.2 ng/ml in acute phase, and then returned to baseline of 136.7+/-52.2 ng/ml in chronic phase. Five patients died of cardiac reasons within 90 days, all of whom had lower IGF-1 on admission and lower IGF-1 in acute phase than their median of 54 patients. Patients with the concentration of IGF-1 on admission below the median (<131 ng/ml) had significantly lower survival rate than those at or above the median (log-rank test p=0.0169). However, patients with BNP concentration at or above the median (> or =227 pg/ml) had a similar survival rate to those below the median (log-rank test p=0.6797). Multivariate analysis clarified that IGF-1 on admission was the sole independent predictor of 90-day mortality (p=0.007, risk ratio=0.927). A low concentration of serum IGF-1 on admission was associated with a poor early prognosis of acute myocardial infarction.


Nuclear morphometry in differential diagnosis of renal oncocytoma and renal cell carcinoma.
Morphometric distinction of renal oncocytoma and renal cell carcinoma was attempted. Nuclear morphometric measurements were done from sections of 16 histologically diagnosed renal oncocytomas and renal cell carcinoma controls (grade 1 or 2, stage T1 to 2N0M0). Oncocytomas could be distinguished from carcinomas on the basis of nuclear morphometry in more than 80% of the cases. Especially, the shape descriptors (form factors) were significantly different between oncocytomas and carcinomas. Morphometrically determined nuclear shape descriptors can be used to support diagnostic decisions in problematic cases.


In vitro and in vivo profiling of fadolmidine, a novel potent alpha(2)-adrenoceptor agonist with local mode of action.
Alpha2-adrenergic receptors (alpha2-adrenoceptors) mediate various physiological actions of endogenous catecholamines in the central and peripheral nervous systems being involved in alertness, heart rate regulation, vasomotor control and nociceptive processing. In the present study, the pharmacological profile of a novel alpha2-adrenoceptor agonist, fadolmidine, was studied in various in vitro and in vivo assays and compared to the well characterised alpha2-adrenoceptor agonist, dexmedetomidine. Fadolmidine displayed high affinity and full agonist efficacy at all three human alpha2-adrenoceptor subtypes (A, B and C) in transfected CHO cells with EC50 values (nM) of 0.4, 4.9 and 0.5, respectively. Fadolmidine inhibited also electrically evoked contractions in rat vas deferens demonstrating the activation of rodent presynaptic alpha2D-adrenoceptors with an EC50 value of 6.4 nM. Moreover, fadolmidine was a full agonist at human alpha1A-adrenoreceptor (EC50 value 22 nM) and alpha1B-adrenoreceptor (EC50 value 3.4 nM) in human LNCaP cells and transfected HEK cells, respectively. Agonism at the alpha1-adrenoceptor was also observed in rat vas deferens preparations although at lower potency (EC50 value 5.6 microM). Fadolmidine demonstrated potent alpha2-adrenoceptor agonist activity also in vivo by inhibiting electrically induced tachycardia in pithed rats and increasing mean arterial pressure in anaesthetised rats. However, after systemic administration, fadolmidine had considerably weaker CNS-mediated effects (mydriasis and sedation) compared to dexmedetomidine possibly due to limited penetration through the blood brain barrier by fadolmidine. In a conclusion, fadolmidine is a potent full agonist at all three alpha2-adrenoceptor subtypes with a pharmacological profile compatible with a therapeutic value e.g. after spinal administration.


Association of native T1 times with biventricular function and hemodynamics in precapillary pulmonary hypertension.
In precapillary pulmonary hypertension (PH) patients, we sought to (1) investigate the relationship between ventricular insertion point (VIP) T1 times, hemodynamic parameters, and biventricular function, and (2) determine the predictors of anterior and inferior VIP T1 time. Twenty-two patients with precapillary PH underwent 1.5-T cardiac MR, right heart catheterization (RHC), and echocardiography. A group of 10 healthy age- and sex-matched volunteers served as controls. Biventricular function, morphology and mass were obtained from short-axis cine images. Native T1 times at anterior, inferior VIP, septum and LV lateral wall were respectively derived from all subjects. Mixed venous oxygen saturation (SvO2) was the strongest hemodynamic parameters correlating with anterior (rp = -0.67, P = 0.001) and inferior VIP T1 time (rp = -0.81, P < 0.001). Elevated VIP T1 times were associated with reduced right ventricular (RV) ejection fraction, RV longitudinal and transverse motion, and increased RV end-diastolic and end-systolic volume index. LV diastolic function, quantified as mitral E velocity, was negatively correlated with anterior, inferior VIP (rp = -0.55, P = 0.01) and septal T1 times (rp = -0.50, P = 0.02), and positively correlated with RV systolic function and wall motion. In multivariate linear regression analyses, systolic eccentricity index (sEI) was the independent predictor of average VIPs T1 time (β= 0.47, P < 0.01), and remained significant correlation after adjustment of RHC and demographic parameters. In patients with precapillary PH, VIP T1 times are associated with biventricular function and hemodynamic parameters. Among all the parameters, sEI acts as a determinant of average VIPs T1 time.


Visual evoked potentials in individuals exposed to long-term low concentrations of toluene.
An investigation of visual evoked potentials was carried out in two groups of subjects; 49 workers employed in a printing-prss where toluene has been used exclusively as an organic solvent for the last 30 years, and 59 workers not occupationally exposed to any known neurotoxic substances. The average length of work service in the printing-press was 21.4 years. The level of exposure was assessed by determination of the concentration of toluene in peripheral blood, the concentration of hippuric acid and ortho-cresol in urine in subgroups of subjects chosen at random from both groups. N75, P100 and N145 waves of the pattern reversal visual evoked potentials were analyzed. In the group of exposed subjects, significantly greater amplitudes were found in all waves, with significantly longer latency of the P100 wave.


The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia.
Trigeminal neuralgia is accompanied by severe mechanical, thermal and chemical hypersensitivity of the orofacial area innervated by neurons of trigeminal ganglion (TG). We examined the role of the voltage-gated sodium channel subtype Nav1.9 in the development of trigeminal neuralgia. We found that Nav1.9 is required for the development of both thermal and mechanical hypersensitivity induced by constriction of the infraorbital nerve (CION). The CION model does not induce change on Nav1.9 mRNA expression in the ipsilateral TG neurons when evaluated 9 days after surgery. These results demonstrate that Nav1.9 channels play a critical role in the development of orofacial neuropathic pain. New routes for the treatment of orofacial neuropathic pain focussing on regulation of the voltage-gated Nav1.9 sodium channel activity should be investigated.


Septal Myectomy in patients with previous coronary revascularization - hypertrophic cardiomyopathy masquerading as ischemic heart disease.
Patients with obstructive hypertrophic cardiomyopathy (HCM) may have symptoms mimicking ischemic heart disease, including chest pain and shortness of breath. Some patients undergo coronary revascularization which may not lead to symptomatic improvement. This study assesses clinical presentations and outcomes of patients with previous coronary revascularization undergoing septal myectomy. From 08/1996 to 07/2017, 166 adult patients with obstructive HCM underwent septal myectomy at our Clinic with a history of percutaneous coronary intervention (PCI, N = 153) or coronary artery bypass grafting (CABG, N = 13). We assessed their functional status before and after coronary intervention and outcomes following myectomy. The median (IQR) age was 65 (59-71) years, and 106 (64%) were male. Among 150 patients whose extent of disease was known, single vessel disease was identified in 109 (73%) who had PCI and 1 (9%) who had CABG. Following revascularization, many (59%) reported no improvement in shortness of breath from preoperative status. Myectomy was performed at a median of 3.2 (1.0-6.3) years following coronary revascularization, and 40 (25%) required myectomy within 1 year. Patients whose shortness of breath persisted after PCI/CABG (N = 90) underwent myectomy earlier than those whose symptoms initially improved (N = 63) after coronary revascularization (1.4 [0.6-4.0] years vs. 5.1 [2.8-9.5] years, p < .001). Almost 25% of patient's required septal myectomy within 1 year of coronary intervention for continued symptoms originally thought to be due to ischemic heart disease. These findings highlight the overlap of obstruction and ischemic symptoms and the importance of complete evaluation for dynamic obstruction in HCM.


Proficiency in neurosurgery.
This evaluation of proficiency is a comparison of other high performance occupations with neurosurgeons, an attempt to understand the minimal number of cases required for proficiency during both residency training and after, and the effect of human factors.


Magnetic Resonance Neurography of the Foot and Ankle.
Peripheral neuropathies of the foot and ankle can be challenging to diagnose clinically due to concomitant traumatic and nontraumatic or degenerative orthopedic conditions. Although clinical history, physical examination, and electrodiagnostic testing comprised of nerve conduction velocities and electromyography are used primarily for the identification and classification of peripheral nerve disorders, MR neurography (MRN) can be used to visualize the peripheral nerves as well as the skeletal muscles of the foot and ankle for primary neurogenic pathology and skeletal muscle denervation effect. Proper knowledge of the anatomy and pathophysiology of peripheral nerves is important for an MRN interpretation.


Excessive force during removal of immigration detainees.
Use of force against immigration detainees during attempts to expel them from the UK must be limited to that which is strictly necessary and proportionate under the circumstances, using accepted methods of restraint designed to minimise injury risk to all concerned. Fourteen cases are reported after failed removal attempts, where there were allegations that excessive force had been employed. Collective analysis of the 14 cases reveals a misuse of handcuffs in 11 cases with resulting nerve injury in 4 cases, the use of inappropriate and unsafe methods of force, such as blows to the head and compression of the trunk and/or neck, and continued use of force even after termination of the deportation attempt, occurring inside security company vehicles out of sight of witnesses. An analysis of the legal implications for the government and recommendations aimed at eradication of abusive practices are given.


Development of neurons containing acetylcholinesterase and cholinacetyltransferase in dispersed cell culture of rat cerebellum.
Cells from one-day-old cerebellum were grown for up to 30 days in dispersed cell culture. The characteristic neurons (deep cerebellar, Golgi and Purkinje cells) maintained their properties. It was found histochemically that some of the large cells display strong AChE activities in the perikaryon and in some processes, while biochemically the specific activities of the marker enzymes of the acetylcholine system, AChE (EC 220.127.116.11) and ChAc (EC 188.8.131.52), were increased and unchanged, respectively. During cultivation, the number of AChE-positive neurons increased. It can be inferred from these studies that, besides the AChE-positive (cholinoceptive) cells, ChAc-active (cholinergic) neurons (possibly Golgi II. type cells and some neurons in the deep cerebellar nuclei) are present in the cerebellum of the rat.


Structure-antifungal activity relationship of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 and analogues.
The synthesis, in vitro evaluation and conformational study of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH(2) and analogues acting as antifungal agents are reported. Among them, His-Phe-Lys-Trp-Gly-Arg-Phe-Val-NH(2) exhibited a moderate but significant antifungal activity against Cryptococcus neoformans, Candida albicans and Candida tropicalis. A theoretical study allows us to propose a biologically relevant conformation for these octapeptides acting as antifungal agents. In addition, these theoretical calculations allow us to determine the minimal structural requirements to produce the antifungal response and can provide a guide for the design of compounds with this biological activity.


Identification of β1,3-galactosyltransferases responsible for biosynthesis of insect complex-type N-glycans containing a T-antigen unit in the honeybee.
Honeybees (Apis mellifera) produce unique complex-type N-glycans bearing a Galβ1-3GalNAc (T-antigen) unit, and honeybee-specific N-glycans are linked to royal jelly glycoproteins. In this study, we identified two novel honeybee β1,3-galactosyltransferase (β1,3-GalT) genes responsible for biosynthesis of the T-antigen in insect N-glycans. The products of the two putative β1,3-GalT genes (β1,3-GalT1 and β1,3-GalT2), which were expressed in Sf21 insect cells, transferred galactose (Gal) residues to GalNAc2GlcNAc2Man3GlcNAc2-PA to form the Galβ1-3GalNAc unit, indicating that the identified genes were involved in biosynthesis of the β1-3 Gal-containing N-glycan. Therefore, using biochemistry and molecular biology techniques, we revealed a unique N-glycan biosynthesis mechanism in the cephalic region of honeybees, which has not previously been found in other animal or plant cells.


Mutation analysis of TCOF1 gene in Chinese Treacher Collins syndrome patients.
Treacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients. We recruited seven TCS families. Variant screening in probands was performed by targeted next-generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software. Three frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285_2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery. We identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families.


Intrauterine exposures and risk of endometriosis.
Intrauterine environmental exposures have been adversely associated with male reproductive health in contrast to limited investigation of such exposures and female reproductive health. To address this research gap, a cohort comprising 84 women aged 18-40 years undergoing laparoscopy was recruited prior to surgery and followed through the post-operative period for endometriosis diagnosis. Women were interviewed about environmental exposures and those of their mothers while pregnant with them (use of alcohol, caffeinated beverages and cigarettes). Endometriosis was diagnosed in 32 women from the laparoscopy cohort; 52 women had no endometriosis visualized. Using unconditional logistic regression, odds ratios (OR) and 95% confidence intervals (CIs) were estimated for the intrauterine exposures adjusting for potential confounders. No significant associations were seen between intrauterine exposure to alcohol or caffeine and a diagnosis of endometriosis. Adjusting for age, significant reductions in odds of an endometriosis diagnosis were observed for intrauterine cigarette exposure both in the absence (OR 0.22, 95% CI 0.06-0.82) or presence (OR 0.05, 95% CI 0.01-0.42) of women's current smoking. While speculative, in utero cigarette exposure may be associated with a lower risk of surgically diagnosed adult-onset endometriosis, possibly as a result of alterations in hormonal milieu or pathologic angiogensis.


Reduced sleep spindles and spindle coherence in schizophrenia: mechanisms of impaired memory consolidation?
Sleep spindles are thought to induce synaptic changes and thereby contribute to memory consolidation during sleep. Patients with schizophrenia show dramatic reductions of both spindles and sleep-dependent memory consolidation, which may be causally related. To examine the relations of sleep spindle activity to sleep-dependent consolidation of motor procedural memory, 21 chronic, medicated schizophrenia outpatients and 17 healthy volunteers underwent polysomnography on two consecutive nights. On the second night, participants were trained on the finger-tapping motor sequence task (MST) at bedtime and tested the following morning. The number, density, frequency, duration, amplitude, spectral content, and coherence of stage 2 sleep spindles were compared between groups and examined in relation to overnight changes in MST performance. Patients failed to show overnight improvement on the MST and differed significantly from control participants who did improve. Patients also exhibited marked reductions in the density (reduced 38% relative to control participants), number (reduced 36%), and coherence (reduced 19%) of sleep spindles but showed no abnormalities in the morphology of individual spindles or of sleep architecture. In patients, reduced spindle number and density predicted less overnight improvement on the MST. In addition, reduced amplitude and sigma power of individual spindles correlated with greater severity of positive symptoms. The observed sleep spindle abnormalities implicate thalamocortical network dysfunction in schizophrenia. In addition, the findings suggest that abnormal spindle generation impairs sleep-dependent memory consolidation in schizophrenia, contributes to positive symptoms, and is a promising novel target for the treatment of cognitive deficits in schizophrenia.


PKG-1α mediates GATA4 transcriptional activity.
GATA4, a zinc-finger transcription factor, is central for cardiac development and diseases. Here we show that GATA4 transcriptional activity is mediated by cell signaling via cGMP dependent PKG-1α activity. Protein kinase G (PKG), a serine/tyrosine specific kinase is the major effector of cGMP signaling. We observed enhanced transcriptional activity elicited by co-expressed GATA4 and PKG-1α. Phosphorylation of GATA4 by PKG-1α was detected on serine 261 (S261), while the C-terminal activation domain of GATA4 associated with PKG-1α. GATA4's DNA binding activity was enhanced by PKG-1α via by both phosphorylation and physical association. More importantly, a number of human disease-linked GATA4 mutants exhibited impaired S261 phosphorylation, pointing to defective S261 phosphorylation in the elaboration of human heart diseases. We showed S261 phosphorylation was favored by PKG-1α but not by PKA, and several other kinase signaling pathways such as MAPK and PKC. Our observations demonstrate that cGMP-PKG signaling mediates transcriptional activity of GATA4 and links defective GATA4 and PKG-1α mutations to the development of human heart disease.


Apoptotic Factors and Mitochondrial Complexes Assist Determination of Strain-Specific Susceptibility of Mice to Parkinsonian Neurotoxin MPTP.
Identification of genetic mutations in Parkinson's disease (PD) promulgates the genetic nature of disease susceptibility. Resilience-associated genes being unknown till date, the normal genetic makeup of an individual may be determinative too. Our earlier studies comparing the substantia nigra (SN) and striatum of C57BL/6J, CD-1 mice, and their F1-crossbreds demonstrated the neuroprotective role of admixing against the neurotoxin MPTP. Furthermore, the differences in levels of mitochondrial fission/fusion proteins in the SN of parent strains imply effects on mitochondrial biogenesis. Our present investigations suggest that the baseline levels of apoptotic factors Bcl-2, Bax, and AIF differ across the three strains and are differentially altered in SN following MPTP administration. The reduction in complex-I levels exclusively in MPTP-injected C57BL/6J reiterates mitochondrial involvement in PD pathogenesis. The MPTP-induced increase in complex-IV, in the nigra of both parent strains, may be compensatory in nature. The ultrastructural evaluation showed fairly preserved mitochondria in the dopaminergic neurons of CD-1 and F1-crossbreds. However, in CD-1, the endoplasmic reticulum demonstrated distinct luminal enlargement, bordering onto ballooning, suggesting proteinopathy as a possible initial trigger.The increase in α-synuclein in the pars reticulata of crossbreds suggests a supportive role for this output nucleus in compensating for the lost function of pars compacta. Alternatively, since α-synuclein over-expression occurs in different brain regions in PD, the α-synuclein increase here may suggest a similar pathogenic outcome. Further understanding is required to resolve this biological contraption. Nevertheless, admixing reduces the risk to MPTP by favoring anti-apoptotic consequences. Similar neuroprotection may be envisaged in the admixed populace of Anglo-Indians.


Magnetic resonance imaging (MRI) in the evaluation of spinal cord injured children and adolescents.
In order to determine the indications and usefulness of MRI scanning in evaluating spinal cord trauma, MRIs on 43 subacute and chronic spinal cord injured children were compared with CT myelograms and other diagnostic tests. MRI scans were superior to CT myelograms in evaluating post-traumatic syrinx, disc pathology and the physiological status of the cord. CT myelogram remains an essential study before considering spinal cord decompression. The presence of internal fixation is not a contraindication to MRI scanning.


Development of supercritical carbon dioxide extraction with a solid phase trap for dioxins in soils and sediments.
A method involving supercritical fluid extraction (SFE) with a solid phase trap containing activated alumina was investigated for the rapid analysis of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin like polychlorinated biphenyls (DL-PCBs) in soils and sediments. The samples were extracted by using supercritical carbon dioxide with water (2% versus CO(2) flow velocity) being used as an entrainer at a pressure of 30 MPa and a temperature of 130 degrees C for 50 min. The extracts were adsorbed on an activated alumina trap that was maintained at a temperature of 150 degrees C, and then, PCDD/DFs and DL-PCBs were eluted with 20 ml of hexane at 60 degrees C. After concentration, they were measured with a high-resolution gas chromatograph interfaced to a high-resolution mass spectrometric detector. The average concentrations of PCDD/DFs and DL-PCBs corresponded to the results obtained by the conventional method, and the reproducibility of this SFE method was below 21% of the relative standard deviations for all samples. The total time required for the analysis of the pretreatment of this method was only 2 h.


Brachytherapy: An emblematic example of extreme hypofractionated regimen.
In order to provide more convenient irradiation regimens for patient comfort, radiation facility organization and health expenses, new hypofractionated protocols have been evaluated. Moderately (dose/fraction: 2.3 to 3Gy), then ultra (dose/fraction: 5.2 to 6.1Gy) hypofractionated irradiations were first validated. The current question is: is it possible to go forward using extreme hypofractionated regimens (EHR) based on 1 to 3 fractions. Different irradiation techniques are under investigation. However, brachytherapy remains the smartest way to deliver a high dose in a small volume. We report prospective and retrospective study results which evaluated EHR for breast and prostate brachytherapy. While oncological outcome and toxicity profile appear extremely encouraging for low-risk breast cancer after a 1 to 4 fractions (6.25 to 20Gy/fraction), the use of a single fraction of 19 to 23Gy appears debatable for prostate cancer. Brachytherapy represents an emblematic example of EHR but longer follow-up and more mature results are awaited in order to specify the right indications and refine the EQD2 calculation method including new biological and technical factors.


First experiences with superfractionated skin irradiations using large afterloading molds.
Radiotherapy of cutaneous metastases of breast cancer requires large radiation fields and high doses. This report examines the effectiveness and sequelae of superfractionated irradiation of cutaneous metastases of breast cancer with afterloading molds on preirradiated and nonirradiated skin. A flexible reusable skin mold was developed for use with a pulsed (PDR) afterloader. An array of 18 parallel catheters was sewn between two foam rubber slabs 5 mm in thickness to provide a defined constant distance to the skin. By selection of appropriate dwell positions, arbitrarily shaped skin areas can be irradiated up to a maximal field size of 17 x 23.5 cm2. Irradiations are performed with a nominal 37 GBq 192Ir stepping source in pulses of 1 Gy/h at the skin surface. The dose distribution is geometrically optimized. The 80 and 50% dose levels lie 5 and 27 mm below the skin surface. Sixteen patients suffering from metastases at the thoracic wall were treated with 18 fields (78-798 cm2) and total doses of 40-50 Gy applying two PDR split courses with a pause of 4-6 weeks. Eleven of the fields had been previously irradiated with external beam therapy to doses of 50-60 Gy at 7-22 months in advance. For preirradiated fields (n = 10) the results were as follows: follow-up 4.5-28.5 months (median 17); local control (LC): 8 of 10; acute skin reactions: Grade 2 (moist desquamation) 2 of 10; intermediate/late skin reactions after minimum follow-up of 3 months: Grade 1 (atrophy/pigmentation): 2 of 10, Grade 2-3a (minimal/marked teleangiectasia): 7 of 10, Grade 4 (ulcer): 1 of 10; recurrencies: 2 of 10. For newly irradiated fields (n = 7) results were: follow-up: 2-20 months (median 5); LC: 6 of 7; acute reactions: Grade 1: 4 of 7, Grade 2: 3 of 7; intermediate/late skin reactions after minimum follow-up of 3 months (n = 5): Grade 2-3a: 2 of 5; recurrencies: 0 of 7. Local control could be achieved in 82% of the mold fields. Geometric optimization was mandatory to achieve a homogeneous dose distribution on the skin. Superfractionated brachytherapy with skin molds is an effective alternative for the treatment of skin metastases of breast cancer even if the skin is preirradiated. This method is economically advantageous compared to external beam therapy, which would require several weeks. At the curved chest wall, optimized molds can provide better dose homogeneity than abutted electron fields. Skin reactions are comparable to the sequelae of orthovolt irradiation. In preirradiated areas, PDR doses should be restricted to 40-45 Gy. PDR doses of 50 Gy seem to be the limit for tolerance even in previously unirradiated fields.


Effects of the antibiotic ciprofloxacin on the bacterial community structure and degradation of pyrene in marine sediment.
The ecological consequences of antibiotics in the aquatic environment have been an issue of concern over the past years due to the potential risk for negative effects on indigenous microorganisms. Microorganisms provide important ecosystem services, such as nutrient recycling, organic matter mineralization and degradation of pollutants. In this study, effects of exposure to the antibiotic ciprofloxacin on the bacterial diversity and pollutant degradation in natural marine sediments were studied using molecular methods (T-RFLP) in combination with radiorespirometry. In a microcosm experiment, sediment spiked with (14)C-labelled pyrene was exposed to five concentrations of ciprofloxacin (0, 20, 200, 1000 and 2000 microgL(-1)) in a single dose to the overlying water. The production of (14)CO(2) (i.e. complete mineralization of pyrene) was measured during 11 weeks. Sediment samples for bacterial community structure analysis were taken after 7 weeks. Results showed a significant dose-dependent inhibition of pyrene mineralization measured as the total (14)CO(2) production. The nominal EC(50) was calculated to 560 microgL(-1), corresponding to 0.4 microg/kg d.w. sediment. The lowest effect concentration on the bacterial community structure was 200 microgL(-1), which corresponds to 0.1 microg/kg d.w. sediment. Our results show that antibiotic pollution can be a potential threat to both bacterial diversity and an essential ecosystem service they perform in marine sediment.


The mammalian RNA polymerase II C-terminal domain interacts with RNA to suppress transcription-coupled 3' end formation.
RNA polymerase II plays a critical role not only in transcription of mRNA precursors but also in their subsequent processing. This later function is mediated primarily by the C-terminal domain (CTD) of the enzyme's largest subunit, a unique, repetitive structure conserved throughout eukaryotes and known to interact with a number of different proteins during the transcription cycle. Here, we show that the mammalian CTD also interacts with RNA in a sequence-specific manner. We use a variety of RNA binding assays, including SELEX, to characterize the interaction in vitro and a modified chromatin immunoprecipitation (ChIP) assay to provide evidence that it also occurs in vivo. Transfection assays with the CTD binding consensus situated downstream of a polyadenylation signal indicate that the sequence can suppress mRNA 3' end formation and transcription termination, and in vitro assays indicate that the inhibition of processing is CTD dependent. Our results provide an unexpected function for CTD in modulating gene expression.


The parasitoid Apanteles kariyai inhibits pupation of its host, Pseudaletia separata, via disruption of prothoracicotropic hormone release.
When the parasitoid Apanteles kariyai laid eggs into host Pseudaletia separata larvae, before prothoracicotropic hormone (PTTH) was released in the last instar preparatory to metamorphosis, the host did not pupate and the larvae of the wasps emerged. The ecdysteroid titer of unparasitized intact larvae increased up to 1 microgram/ml 1 day before pupation, whereas the titer of parasitized larvae was maintained at a low level without the surge. Isolated prothoracic glands from intact larvae synthesized much more ecdysone than those of parasitized larvae both in vivo and in vitro. Administration of exogenous PTTH caused the activation of the prothoracic glands seen during parasitization. Injection of 20-hydroxyecdysone (20-HE) into the parasitized larvae caused by host's pupation, but did not affect the development of the wasp larvae. However, the sensitivity of the integument to 20-HE was lower in parasitized than in unparasitized larvae. Injection of a mixture of adult wasp calyx and venom fluids into last instar unparasitized larvae delayed their pupation, suggesting that calyx and venom fluids are factors contributing to disturbance of the normal function of brain-prothoracic gland system. These results show that parasitization inhibits secretion and/or synthesis of PTTH and also delays the larval-pupal commitment of the integument by keeping the ecdysteroid level low.


Accuracy on the preoperative assessment of patients with adolescent idiopathic scoliosis using biplanar low-dose stereoradiography: a comparison with computed tomography.
Although computed tomography (CT) is commonly used to diagnose the scoliotic spine in patients with adolescent idiopathic scoliosis (AIS) preoperatively, it is limited by the high radiation and prone scanning position. Recently, a new biplanar stereoradiography (EOS) was used to image the scoliotic spine in an upright posture with significantly less radiation in non-severe AIS subjects. However, its reliability to assess preoperative AIS patients remains unreported. Hence, the purpose of this study is to compare the scoliotic curvature between prone (CT) and upright positions (EOS) in preoperative AIS patients. Thirty-three pre-operative AIS patients (mean age:18.4 ± 4.2) were recruited. EOS was used to scan the whole thoracic spine at upright position. Whereas on the same day, a conventional CT scan was used to evaluate the spine in prone position. The three-dimensional reconstruction of EOS and CT of the spine were then generated. Using previous validated techniques, multiple scoliotic parameters in both modalities were determined. The agreement between the two modalities was compared using the Bland-Altman test, whereas the correlation was assessed by the intraclass correlation coefficient (ICC). The mean ICC (prone and upright) of intra-rater/inter-rater reliabilities for the measured parameters were 0.985,0.961/0.969,0.903, respectively. Thoracic Cobb angles, intervertebral wedging and lumbar lordosis correlated significantly between upright EOS imaging radiographs (62.9 ± 9.3°,6.4 ± 2.9° and 48.8 ± 12.4°) and prone CT (47.3 ± 10.0°,5.8 ± 2.7° and 27.9 ± 11.4°; P < 0.001). The apical vertebral wedging and apical intervertebral disc wedging showed a good correlation among the two modalities (upright, 6.5 ± 3.5° and 6.4 ± 2.9°; prone, 6.5 ± 3.6° and 5.8 ± 2.7°; R2 ≥ 0.94; P < 0.01). Similarly, there was significant correlation in apical intervertebral rotation (R2 = 0.834; P < 0.01) between the prone CT (3.4 ± 3.0°) and upright EOS (3.8 ± 3.2°). In addition, the Cobb angle was significantly larger in upright EOS (62.9 ± 9.3°) than in prone CT (47.3 ± 10.0°, P < 0.01) position. There was significant underestimation on scoliotic severity in the prone position when compared with upright position. Importantly, the image acquisition and reconstruction from EOS can better provide accurate three-dimensional spinal representations of the scoliotic curvature in preoperative AIS patients. Moreover, our findings suggested that scoliotic curvatures in preoperative AIS patients can be largely represented by both imaging modalities despite the difference in body positioning.


Pelvic Floor Biofeedback via a Smart Phone App for Treatment Of Stress Urinary Incontinence.
Biofeedback can be useful for treatment of stress urinary incontinence. Many women have difficulty isolating their pelvic floor muscles and adhering to a daily exercise regimen. This case study highlights a woman's experience using PeriCoach, a home biofeedback device that assists women in strengthening their pelvic floor muscles through Bluetooth technology using a smartphone.


X-linked retinoschisis: a clinical and molecular genetic review.
X-linked retinoschisis is a leading cause of macular degeneration in male children. It is characterized by a high degree of clinical variability. Clinical features include a stellate foveal retinoschisis, with or without peripheral retinoschisis. The schisis occurs within the inner retina, primarily at the level of the nerve fiber layer. The disease-causing gene, X-linked retinoschisis 1, has recently been identified, and is expressed in photoreceptor and bipolar cells. This gene codes for retinoschisin, a secreted protein containing a discoidin domain which may be involved in cellular adhesion or cell-cell interactions. The identification of this gene allows for improved diagnosis and contributes to the understanding of this condition. Visual prognosis is variable, as X-linked retinoschisis exhibits a high degree of phenotypic variability. Although there is no treatment to halt the progressive maculopathy, clinical management is directed toward treatment of amblyopia and surgical correction of certain complications. X-linked retinoschisis is an important condition to study, both to improve the clinical management of this disorder, and to better understand retinal function and development. Herein, we review the clinical, histopathologic, and molecular genetic and treatment options of X-linked retinoschisis.


Human fibroblast interferon for clinical trials: pharmacokinetics and tolerability in experimental animals and humans.
Human fibroblast interferon (F-interferon) purified by adsorption on controlled-pore glass was given intramuscularly to patients at daily dosages of up to 20 x 10(6) units. Serum levels of antiviral activity were low or undetectable. In contrast, reasonably high serum titers were found in patients receiving interferon prepared from leukocytes (L-interferon). Similarly, in rabbits lower serum titers were seen with F-interferon than with L-interferon. These results are at variance with those obtained earlier (V. G. Edy, A. Billiau, and P. De Somer, J. Infect. Dis. 133:A18-A21, 1976). Possible explanations for this discrepancy are discussed. The F-interferon evoked febrile reactions, delayed skin reactivity, and transitory lymphopenia in humans. Some patients developed an allergic state of the reaginic type as evidenced by a weal and flare reaction after intradermal challenge. However, these patients did not show allergic symptoms after intramuscular injections. None of the side effects was severe enough to prohibit continuation of the treatment; most of them seemed to be due to contaminants not removed by the purification method. The possibility is considered that some of the side effects, e.g., delayed skin reactivity, are sufficiently specific to justify identification of the active principals.


Fixed dosing of kukoamine B in sepsis patients: Results from population pharmacokinetic modelling and simulation.
To assess the appropriateness of the body weight or fixed dosing regimen, a population pharmacokinetic (PopPK) model of kukoamine B has been built in sepsis patients. Plasma concentrations of kukoamine B and the covariates information were taken from 30 sepsis patients assigned into 0.06 mg/kg, 0.12 mg/kg and 0.24 mg/kg groups in a Phase IIa clinical trial. The PopPK model was built using a nonlinear mixed-effect (NLME) modelling approach. Based on the final model, PK profiles were respectively simulated 500 times applying the body weight and renal function information of 12 sepsis patients from the 0.24 mg/kg group on the body weight or the fixed dosing regimen. For each dosing regimen, PK profiles of 6000 virtual patients were obtained. Statistical analyses for Cmax and Cmin were performed. If the biases of Cmax and Cmin can all meet the criteria of ±15%, the fixed dosing regimen can substitute for the body weight dosing regimen. The PopPK model was successfully developed using the NLME approach. A bi-compartmental model was selected as the basic model. Renal function was identified as a statistically significant covariate of systemic clearance with the objective function value (OFV) decreasing 8.6, resulting in a 5.2% decrease in inter-individual variability (IIV) of systemic clearance. Body weight was not identified as a statistically significant covariate. Simulation results demonstrated two methods had a bias of 8.1% for Cmax , and 8.6% for Cmin . Furthermore, PK variability was lower on the fixed dosing regimen than the body weight regimen. Based on the simulation results, a fixed dosing regimen was recommended in the subsequent clinical trials.


Priorities for sexual and reproductive health in Morocco as part of universal health coverage: maternal health as a national priority.
Maternal health (MH) is a national priority of Morocco. Factors influencing the agenda set by the reproductive and maternal health policy process at the national level were evaluated using the Shiffman and Smith framework. This framework included the influence of the actors, the power of the ideas used, the nature of the political context, and the characteristics of the issue itself. Factors were evaluated by a review of documents and interviews with policy-makers, partners and individuals in the private sector, civil society and non-governmental organisations (NGOs) involved in MH, and decision-makers responsible for implementing health-financing strategies in Morocco. Evaluations showed that maternal mortality in Morocco was considered human rights and social development as well as a public health problem. The actors responsible for MH, including members of the government, researchers, national technical experts, members of the private sector, United Nations partners and NGOs, agreed on progress made in MH and universal health care (UHC). Stakeholders also agreed on the prioritisation process for MH and its inclusion in the health benefits package. Prioritisation of MH was found to depend on national health priorities set by the government and its close partners, as well as on the availability of human and financial resources. Interventions at the operational level were based on evidence, best practices, allocation of adequate financial and human resources, and rigorous monitoring and accountability. However, MH and health financing are experiencing difficulties in many areas, related to social and economic and health disparities, and gender inequality, and quality of care.


Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells.
Trastuzumab (Herceptin), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab.


[Behcet's disease--ophthalmological and general aspects: Part 2: Therapy].
Behcet's disease (also called Admantiades-Behcet syndrome) is a chronic vasculitis. The disease is characterized by exacerbations and remissions of symptoms and organ manifestations and may produce only mild mucocutaneous lesions, whereas ocular lesions can cause blindness. In addition, involvement of the gastrointestinal tract, central nervous system (CNS) and large blood vessels is sometimes life-threatening. Cyclosporin A is the only agent for treatment of ocular lesions registered in Germany; however, the neurotoxicity and nephrotoxicity restrict usage of the drug. In patients suffering from severe uveitis, biologics have been a breakthrough. Interferon (IFN) alpha therapy has shown significant efficacy for intraocular inflammation. Monoclonal antibodies to TNF-alpha and interleukin-1 have been successful in clinical trials and are approved in some countries. This article summarizes the current state of knowledge and emphasizes the important role of the ophthalmologist in the therapy of Behcet's disease.


Immunophenotyping in the diagnosis and classification of acute lymphoblastic leukemia.
The identification of ALL immunophenotypes with distinctive clinical features and prognostic significance indicates the importance of these studies in the evaluation of ALL patients for both clinical and research purposes. For differential diagnosis, the expression of pan-B-cell or pan-T-cell lymphoid antigens and the absence of myeloid/monocyte antigens represent the most useful markers for distinguishing ALL from AML. However, the increasing appreciation of large numbers of patients with clinically significant mixed lymphoid-myeloid phenotypes suggests that rigid classification of acute leukemias into exclusive lymphoid and myeloid categories may be somewhat artificial. In adult ALL, patients with My+ phenotypes (B+sIg-T-My+ and B-sIg-T-My+) have a lower incidence of complete remission and shorter survival times than do patients with My- marker profiles. Preliminary studies in childhood ALL also suggest a correlation between myeloid antigen expression and poor prognostic factors. In addition, children with sIg+ "B-cell," cIg+ "pre-B-cell," and T-cell ALL phenotypes have shorter disease-free survival times than do patients with more common "early pre-B" (B+cIg-sIg-T-) marker profiles. Application of immunologic markers in concert with cytogenetic and gene rearrangement studies has led to the identification of novel subgroups of leukemia with distinct clinical characteristics. Future studies incorporating a multiparameter diagnostic approach including immunophenotyping, gene rearrangement studies, and karyotypic analyses should further our understanding of the heterogeneity of acute leukemias, guide the development of new therapeutic strategies, and provide for more clinically relevant classification of these disorders.


Laparoscopic repair of inguinal cystocele using cystoscopic light test.
To describe how the cystoscopic light test aids in the repair of inguinal bladder herniation. After the diagnosis of a bladder herniation into the right inguinal canal using intravenous pyelography, laparoscopic repair was planned. A cystoscope was manipulated into the defect while turning off the laparoscopic light intra-abdominally. The light of the cystoscope could be identified through the cystocele, and the neck of the hernia was easily recognized. Once the bladder was reduced, the cystoscope was replaced, and reduction of the herniation was confirmed. We were able to successfully reduce the bladder herniation without recurrence at 24 months of follow-up. The cystoscopic light test represents a useful tool in the recognition of an inguinal bladder herniation, before, during, and after the definitive repair of the defect.


Detection and assay of organophosphate pesticides in human blood by gas chromatography.
Gas chromatography was used in blood samples for determining human exposure to organophosphate insecticides. The identification is difficult beyond 48 hr after exposure because of the high reactivity of these compounds.


The Lacuna Trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant.
To determine tolerability of bovine lactoferrin (bLF) in very preterm infants, and whether the intervention can be adequately masked. In a single-center masked pilot trial infants under 31 weeks gestation were randomized before 48 h of age to receive milk with 100 mg per day of bLF or control. The primary outcome was feeding tolerance, defined as time to achieve full feeds (140 ml kg(-1) per day). Parents answered a short questionnaire regarding acceptability of the intervention. Seventy-nine infants were enrolled and analyzed according to intention to treat. There was no effect of bLF on the primary outcome. In addition, mortality, late onset sepsis and other complications of prematurity were no different. Equal numbers of parents in both groups believed their infant received bLF. We demonstrated that bLF is well tolerated, easy to administer and its presence in prepared milk is not evident. Trial registration number ISRCTN66482337.


Naturally existing isoforms of miR-222 have distinct functions.
Deep-sequencing reveals extensive variation in the sequence of endogenously expressed microRNAs (termed 'isomiRs') in human cell lines and tissues, especially in relation to the 3' end. From the immunoprecipitation of the microRNA-binding protein Argonaute and the sequencing of associated small RNAs, we observe extensive 3'-isomiR variation, including for miR-222 where the majority of endogenously expressed miR-222 is extended by 1-5 nt compared to the canonical sequence. We demonstrate this 3' heterogeneity has dramatic implications for the phenotype of miR-222 transfected cells, with longer isoforms promoting apoptosis in a size (but not 3' sequence)-dependent manner. The transfection of longer miR-222 isomiRs did not induce an interferon response, but did downregulate the expression of many components of the pro-survival PI3K-AKT pathway including PIK3R3, a regulatory subunit whose knockdown phenocopied the expression of longer 222 isoforms in terms of apoptosis and the inhibition of other PI3K-AKT genes. As this work demonstrates the capacity for 3' isomiRs to mediate differential functions, we contend more attention needs to be given to 3' variance given the prevalence of this class of isomiR.


Genital papillomavirus in Greek women with high-grade cervical intraepithelial neoplasia and cervical carcinoma.
Fifty biopsies from high-grade squamous intraepithelial lesions (HG-SIL) and 14 cervical carcinoma biopsies from Greek women were screened for the presence of human papillomavirus (HPV) DNA sequences by Southern blot hybridization and by the polymerase chain reaction (PCR) for the presence of different HPV types. In high-grade SIL, HPV DNA sequences were detected in 44 of 50 biopsies with the following distribution: 36% HPV 16, 12% HPV 18, 6% HPV 31, 6% HPV 33, 4% HPV 51, and 24% unclassified HPV types. In cervical carcinoma biopsies, 13 of 14 specimens were positive for HPV DNA sequences. Six biopsies were positive for HPV 16, three were positive for HPV 18, and four contained unclassified HPV types. Overall, of the total 64 biopsies, 57 (89%) were positive for HPV DNA sequences. Of these, Southern blot hybridization alone detected HPV DNA sequences in 39 cases, whereas by PCR 18 additional specimens were found to be positive for HPV. Among the HPV 16-positive biopsies, two samples produced a Pstl banding pattern very similar but not identical to that of HPV 16 prototype and were referred to as HPV 16 isolates. One HPV 16 isolate appears to carry a mutation within the carboxy-terminal half of the L2 gene that results in the loss of a Pstl site. The other HPV 16 isolate had a similar Pstl banding pattern to that previously reported as HPV 16 "variant" found in Cape Town [Williamson et al., 1989, Journal of Medical Virology 28: 146-149, 1994, Journal of Medical Virology 43: 231-237.] and in Italy [Li Vigni et al., 1994, 2nd International Congress of Papillomavirus in Human Pathology (Abstracts), p 100.].


Introital and transvaginal ultrasound as the main tool in the assessment of urogenital and pelvic floor dysfunction: an imaging panel and practical approach.
This article reviews the different applications of ultrasound in benign urogynecological diseases. The findings presented here were obtained by introital and transvaginal ultrasound, both of which can be performed with the same equipment (5-7-MHz sector transducer, emission angle of at least 90 degrees; for introital sonography, the transducer is placed over the external urethral orifice with the transducer axis corresponding to the body axis). Female voiding dysfunction, including urge symptoms, recurrent urinary tract infections and urinary incontinence, may occur secondary to morphological and topographical changes of the urogenital organs. Findings such as urethral diverticula, periurethral masses, funneling of the urethra and distension cystoceles are identified by introital ultrasound. Transvaginal ultrasound enables the detection of pathologies of the bladder and uterus including its appendages. Ultrasound as part of the diagnostic work-up of stress urinary incontinence and genitourinary prolapse allows for the morphological and dynamic assessment of the lower urinary tract. It is possible, for example, to classify sonographically identified changes of the endopelvic fascia as lateral (distraction cystocele, funneling of the urethra) and central (pulsation cystocele) defects as well as to determine the reactivity of the pelvic floor muscles. Ultrasound has replaced radiography in yielding information on the abnormal morphology of the urogenital organs, which should be taken into account in planning the treatment of urogynecological conditions.


Instantaneous systems of communicative conventions through virtual bargaining.
People can instantaneously create novel conventions that link individual communicative signals to meanings, both in experiments and everyday communication. Yet a basic principle of natural communication is that the meaning of a signal typically contrasts with the meanings of alternative signals that were available but not chosen. That is, communicative conventions typically form a system, rather than consisting of isolated signal-meaning pairs. Accordingly, creating a novel convention linking a specific signal and meaning seems to require creating a system of conventions linking possible signals to possible meanings, of which the signal-meaning pair to be communicated is merely a sub-case. If so, people will not link signals and meanings in isolation; signal-meaning pairings will depend on alternative signals and meanings. We outline and address theoretical challenges concerning how instantaneous conventions can be formed, building on prior work on "virtual bargaining," in which people simulate the results of a process of negotiation concerning which convention, or system of conventions, to choose. Moreover, we demonstrate empirically that instantaneous systems of conventions can flexibly be created in a 'minimal' experimental paradigm. Experimental evidence from 158 people playing a novel signaling game shows that modifying both the set of signals, and the set of meanings, can indeed systematically modify the signal-meaning mappings that people may instantaneously construct. While consistent with the virtual bargaining account, accounting for these results may be challenging for some accounts of pragmatic inference.


Increased removal rate of exogenous triglycerides after prolonged exercise in man: time course and effect of exercise duration.
Ten healthy young men exercised for 1.5 and 3 hours, respectively, 4 to 6 weeks apart at the same work intensity, corresponding to 77% of the individual maximal heart rate. In the fasting state 1 mL of 10% Intralipid/kg body weight was injected IV, the fractional removal rate was calculated (k2-value), and fasting lipid and apolipoprotein C-I, C-II, and CIII concentrations were determined one day before, immediately before, immediately after, and one day after the exercise: measurements were also made two and three days after the three-hour session. An increase of the k2-value was found only the day after the three-hour exercise (+66%, P less than .01), while after the 1.5-hour exercise the k2-value was not changed. One and two days after the three-hour exercise the fasting serum triglyceride concentration was significantly decreased by 33% and 16%, respectively. Serum triglyceride concentration was decreased also the day after the shorter session (-17%, P less than .05). Decreases in serum cholesterol concentrations were significant after both exercise bouts, but the significance disappeared if corrections for the changes in calculated plasma volume were made. Serum level of C apolipoproteins was decreased one day after the three-hour exercise, while it was not changed after the shorter exercise. This study shows that prolonged exercise produces an increase in the removal rate of Intralipid triglycerides from the bloodstream, that this change is related to the duration of exercise, and that some time is required following the exercise, before it is manifest.


Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli.
Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.


Comprehensive History and Physicals are Common Before Low-Risk Surgery and Associated With Preoperative Test Overuse.
The Centers for Medicare and Medicaid Services (CMS) recently eliminated the requirement for preoperative history and physicals (H&Ps) prior to ambulatory surgery. We sought to assess variations in separately billed preoperative H&P utilization prior to low-risk ambulatory surgery, describe any relationship with preoperative testing, and identify independent predictors of these consultations prior to this policy change to help characterize the potential unnecessary utilization of these consultations and potential unnecessary preoperative testing prior to low-risk surgery. A retrospective cohort study was performed using claims data from a hospital value collaborative in Michigan from January 2015 to June 2019 and included patients undergoing one of three ambulatory procedures: breast lumpectomy, laparoscopic cholecystectomy, and laparoscopic inguinal hernia repair. Rates of preoperative H&P visits within 30 d of surgical procedure were determined. H&P and preoperative testing associations were explored, and patient-level, practice-level, and hospital-level determinants of utilization were assessed with regression models. Risk and reliability-adjusted caterpillar plots were generated to demonstrate hospital-level variations in utilization. 50,775 patients were included with 50.5% having a preoperative H&P visit, with these visits being more common for patients with increased comorbidities (1.9 ± 2.2 vs 1.4 ± 1.9; P < 0.0001). Preoperative testing was associated with H&P visits (57.2% vs 41.4%; P < 0.0001). After adjusting for patient case-mix and interhospital and intrahospital variations in H&P visits, utilization remained with significant associations in patients with increased comorbidities. Preoperative H&P visits were common before three low-risk ambulatory surgical procedures across Michigan and were associated with higher rates of low-value preoperative testing, suggesting that preoperative H&P visits may create clinical momentum leading to unnecessary testing. These findings will inform strategies to tailor preoperative care before low-risk surgical procedures and may lead to reduced utilization of low-value preoperative testing.


Impact of perceived rearing and social support on bonding failure and depression among mothers: A longitudinal study of pregnant women.
Although previous studies have reported associations between bonding failure, depression, social support among mothers, and perceived rearing, the causal relationships remain unclear. A total of 855 women (mean age, 32.4 ± 4.4 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), the Japanese version of the Social Support Questionnaire, and the Parental Bonding Instrument in early pregnancy before week 25 (T1) and at 1 month after delivery (T2). We created a path model to clarify the causal relationships between perinatal bonding failure, depression, social support, and perceived rearing during pregnancy and at 1 month after delivery. The model was tested using structural equation modeling. Our recursive model showed acceptable fit (chi-squared statistic/degree of freedom = 2.1, comparative fit index = 0.98, root mean square error of approximation = 0.04). It was revealed that: (1) at T1, higher overprotection significantly predicted MIBQ scores; (2) at T1, poorer social support significantly predicted both MIBQ and EPDS scores; and (3) at T1, both MIBQ and EPDS scores significantly predicted respective scores at T2. These results showed that bonding failure in the postpartum period was significantly influenced by mothers' own perceived rearing and social support during pregnancy. In addition, depression in the postpartum period was strongly influenced by social support during pregnancy. These findings suggest that psychosocial interventions that focus on both mothers' recollections of their own upbringing and social support during pregnancy are effective for preventing bonding failure and depression in the postpartum period.


Experimental studies on factors causing acute serum sickness glomerulonephritis of immune complex origin. I. The role of immune complexes and the immunological status of the host.
In acute serum sickness glomerulonephritis induced in rabbits by large doses of BSA, the relationship of the host's immunological status and the severity of renal histological changes was studied. It was found that good antibody producers developed more severe renal lesions. The higher avidity of antibodies enhances the inflammatory effect of immune complexes. Kidney is favoured for deposition of immune complexes especially in the case of chronic immune complex formation in the presence of antigen excess. Diminished phagocytic function of leukocytes (probably decreased immune complex saturating capacity) may also contribute to the severity of renal histological alterations.


Quantitative in vivo proton MR spectroscopic evaluation of the irradiated rat brain.
To investigate if in vivo localized proton magnetic resonance spectroscopy (MRS) can detect putative metabolic changes in the irradiated rat brain and quantitatively measure brain metabolite changes in this model. A total of 20 adult male Fischer 344 rats were exposed to a fractionated regimen of whole brain irradiation (WBI) (total 45 Gy, given as five Gy fractions, twice per week for 4.5 weeks); 10 control rats received sham irradiation. A total of 52 weeks after WBI, all animals were subjected to high-resolution MRI and in vivo proton MRS to determine structural and brain metabolite changes. Brain metabolites were measured by using single-voxel MRS. Quantitative analysis of detectable metabolites was performed by using the spectral analysis method, LCModel. Significant differences in brain metabolite concentrations were detected in rat brains irradiated with a clinically relevant fractionated radiotherapy regimen in 52 weeks, in comparison to age-matched sham-irradiated rats. These findings indicate that quantitative in vivo MRS may serve as a sensitive imaging tool to noninvasively detect neurochemical changes in the irradiated brain.


Fluid mechanical dispersion of airborne pollutants inside urban street canyons subjecting to multi-component ventilation and unstable thermal stratifications.
The pedestrian level pollutant transport in street canyons with multiple aspect ratios (H/W) is numerically investigated in the present work, regarding of various unstable thermal stratification scenarios and plain surrounding. Non-isothermal turbulent wind flow, temperature field and pollutant spread within and above the street canyons are solved by the realizable k-ε turbulence model along with the enhanced wall treatment. One-vortex flow regime is observed for shallow canyons with H/W=0.5, whereas multi-vortex flow regime is observed for deep canyons with H/W=2.0. Both one-vortex and multi-vortex regimes could be observed for the street canyons with H/W=1.0, where the secondary vortex could be initiated by the flow separation and intensified by unstable thermal stratification. Air exchange rate (AER) and pollutant retention time are adopted to respectively evaluate the street canyon ventilation and pollutant removal performance. A second-order polynomial functional relationship is established between AER and Richardson number (Ri). Similar functional relationship could be established between retention time and Ri, and it is only valid for canyons with one-vortex flow regime. In addition, retention time could be prolonged abruptly for canyons with multi-vortex flow regime. Very weak secondary vortex is presented at the ground level of deep canyons with mild stratification, where pollutants are highly accumulated. However, with the decrease of Ri, pollutant concentration adjacent to the ground reduces accordingly. Present research could be applied to guide the urban design and city planning for enhancing pedestrian environment.


Findings of Case-Study Analysis: System-Level Biomimicry in Built-Environment Design.
Complex systems challenges like those facing 21st-century humanity, require system-level solutions that avoid siloed or unnecessarily narrow responses. System-level biomimicry aims to identify and adopt design approaches that have been developed and refined within ecosystems over 3.8 billion years of evolution. While not new, system-level biomimetic solutions have been less widely applied in urban design than the 'form' and 'process' level counterparts. This paper explores insights from a selection of system-level case studies in the built environment, using meta-analysis to investigate common challenges and priorities from these projects to support knowledge-sharing and continued development in the field. Using a grounded research approach, common themes are distilled, and findings presented regarding success and barriers to implementation and scaling. Considering the findings, and drawing on complex adaptive systems theory, the paper posits opportunities to facilitate broader implementation and mainstreaming of system-level biomimetic design approaches in the built environment.


An immunochemical and immunocytologic study of the increase in myometrial gap junctions (and connexin 43) in rats and humans during pregnancy.
Myometrial gap junctions are thought to play a necessary role in control of parturition. In this study we evaluated the presence of gap junctions in myometrial tissues with a specific antibody to the gap junction protein, connexin 43, with immunocytochemistry and immunoblots. Immunofluorescence of rat heart showed gap junctions were localized along the intercalated disks, but no change occurred during pregnancy. Fluorescent staining of rat myometria showed punctate staining of gap junctions between muscle cells during term and preterm birth, illustrating the tremendous increase in gap junctions during labor. Similarly, staining of human myometrial tissues was present in specimens from pregnant patients but absent in tissues from nonpregnant women. Immunoblots of myometrial tissues from rat and humans confirmed the existence of high levels of connexin 43 during term and preterm labor in rats and also during late pregnancy in humans.


An efficient production of hybrid recombinant protein comprising non-structural proteins (NS 1 & NS 3) of bluetongue virus in prokaryotic expression system.
Strategic design and suitable purification techniques are of paramount importance in the production of recombinant proteins, if intended for use in a diagnostic assay. However, there is no single protocol that can be universally adopted for obtaining proteins in requisite quality and quantity across various platforms. In this study, we have targeted proteins of bluetongue virus (BTV), which is the causative agent of an arthropod-borne infectious disease in ruminants. Traditionally, serological diagnosis of the disease has rested upon either virus neutralization test or on an ELISA test that employed a recombinant structural (VP1, VP7) protein. Among the non-structural (NS) proteins of BTV, NS1 and NS3, are preferred candidate antigens in development of immuno-diagnostics as these provide the option for identifying recent/ongoing infection. However, the difficulty in production/purification of recombinant full length NS proteins of BTV in sufficient quantity and quality in various expression systems, due to inherent structural complexities, have restricted their wider applicability as immunodiagnostic reagents. To circumvent the difficulties associated with production/purification, we developed a novel NS1 and NS3 fusion gene (∼1302 bp) encoding for NS1 N-terminus (1M to G252 aa) and NS3 protein containing the N- and C-termini with a deletion of two hydrophobic domains along with intervening variable central domain (118A to A182 aa) of bluetongue virus 23. This construct was cloned, over-expressed and efficiently purified by single step affinity chromatography under unique denaturing/renaturing condition. The purified fusion protein was found suitable for detection of antibodies against BTV in an indirect ELISA (iELISA).


Superior Canal Dehiscence Involving the Superior Petrosal Sinus: A Novel Classification Scheme.
To highlight superior semicircular canal dehiscence (SSCD) involving the superior petrosal sinus (SPS), and to propose a novel classification system for SPS associated SSCD with potential surgical implications. Multicenter retrospective review. Three tertiary referral centers. All patients diagnosed with SPS associated SSCD (1/2000 to 8/2016). Radiographic findings and clinical symptoms were analyzed. Surgical repair or observation. Radiographic findings and clinical symptoms were analyzed. Thirty-three dehiscences (30 patients) involving the SPS were identified. The average age at the time of presentation was 52.5 years (median, 56.9; range, 4.9-75.3 yr), and 53.3% of patients were men. Three patients had bilateral SPS associated SSCD. The most common associated symptoms at presentation were episodic vertigo (63.6%), subjective hearing loss (60.6%), and aural fullness (57.6%). Four distinct types of dehiscence were identified: class Ia. SSCD involving a single dehiscence into an otherwise normal appearing SPS; class Ib. SSCD involving a single dehiscence into an apparent venous anomaly of the SPS; class IIa. SSCD involving two distinct dehiscences into the middle cranial fossa and the SPS; class IIb. SSCD involving a single confluent dehiscence into the middle cranial fossa and the SPS. SSCD involving the SPS represents a small but distinct subset of SSCD cases. This scenario can create a unique set of symptoms and surgical challenges when intervention is sought. Clinical findings and considerations for surgical intervention are provided to facilitate effective diagnosis and management.


Phenotypic screening identifies hydroxypyridone anti-fungals as novel medicines for the prevention of hypertrophic scars.
Although hypertrophic scarring affects ∼91% of burn patients annually, there is no drug to prevent this common complication. Hypertrophic scars are a result of dysregulated wound healing, characterised by persistent myofibroblast transformation and the excessive accumulation of extracellular matrix (ECM). Due to the multi-mechanistic nature of the scarring process, target-based approaches for identifying novel drugs have failed. Primary human dermal fibroblasts, derived from burn scar tissue, were exposed to transforming growth factor-beta 1 (TGF-β1) to induce myofibroblast transformation. A phenotypic screening assay, measuring alpha-smooth muscle actin (α-SMA) expression, was developed to screen 1,954 approved drugs. Drugs that elicited >80% inhibition of α-SMA expression, and >80% cell viability were progressed as candidate drugs. Anti-myofibroblast activity of the candidates was confirmed before investigating their effects on extracellular matrix (ECM) production and keratinocyte epithelial-mesenchymal transition (EMT). TGF-β1 induced myofibroblast transformation in primary human dermal fibroblasts (Emax = >3 ng/mL). The assay was optimised and validated (Z' = 0.59), before screening 1,954 approved drugs. 90 drugs were identified as hits and hydroxypyridone anti-fungals selected for further testing. Concentration-response curves for these drugs confirmed their concentration-dependent anti-myofibroblast activity (IC50 = 1.4 - 16.7 μM). Hydroxypyridone anti-fungals were also found to successfully reduce ECM production and keratinocyte EMT. This is the first study to screen approved drugs in primary human dermal fibroblasts. Hydroxypyridone anti-fungals were found to prevent myofibroblast transformation, ECM production and keratinocyte EMT suggesting they could be repurposed to prevent hypertrophic scarring.


Identification of germ cell-specific VASA and IFITM3 proteins in human ovarian endometriosis.
Endometriosis is a gynaecological disorder that affects 6-10 % of female population. It is characterized by the presence of endometrial tissue outside the uterus, most often in the pelvic peritoneum or ovaries. Recent studies have indicated that mesenchymal endometrial stem cells might get involved in endometriosis progression. Although germ line stem cells have been proved to exist in the ovary, their involvement in ovarian endometriosis has not been investigated. In this preliminary report we aimed to identify germinal stem cell markers in ovarian endometriosis. Ten paraffin-embedded ovarian endometriosis samples were screened for germ cell-specific proteins DDX4 (VASA) and IFITM3, and its relation with stem cell marker OCT4, proliferation marker PCNA and estrogen receptor alpha (ESR1), by immunohistochemistry, immunofluorescence and PCR. DDX4 and IFITM3 proteins were expressed in isolated cells and clusters of cells in the cortical region of ovarian endometriotic cysts. DDX4 and IFITM3 co-localized in cells from endometriotic stroma, and DDX4/IFITM3-expressing cells were positive for ESR1, OCT4 and PCNA. No cells expressing neither DDX4 nor IFITM3 were detected in normal endometrial tissue. The identification of germ cell-specific proteins DDX4 and IFITM3 provides the first evidence of ovarian-sourced cells in ovarian endometriotic lesions and opens up new directions towards understanding the still confusing pathogenesis of endometriosis.


Elucidation of the mechanisms of hairy-cell localization in tissues and the process of the bone marrow fibrosis in hairy-cell leukemia.
Hairy cell leukemia is a chronic B cell leukemia with a number of distinctive features including the unusual tissue distribution of the leukemic cells, hairy cells, and the bone marrow fibrosis. We have been working, for a number of years, on the potential mechanisms behind hairy-cell localization in tissues. In this review, it is summarized how our work has shed very important information regarding these mechanisms and led, eventually, to the full elucidation of the process of the bone marrow fibrosis in hairy cell leukemia.


Testicular seminoma: histological findings and their prognostic significance for stage II disease.
Risk factors, their interrelationship, and prognostic relevance for seminoma stage II disease have been examined. The size of the primary tumor was significantly correlated with the pT category, as was the presence of tumor invasion of small vessels. The pT category was correlated neither with clinical substage nor relapse rate. There was a poorer 3-year survival for anaplastic seminomas as compared to that of classical seminomas; the difference was not significant. The 5-year survival for seminomas rich in lymphocytes was better than those of poor lymphocytic infiltration, but this difference also was not significant. No difference in survival or relapse rate was found between HCG-producing and HCG-nonproducing seminomas.


Carcinogenesis of nitrosomethylundecylamine in Fischer rats.
Nitrosomethylundecylamine was synthesized and administered to Fischer rats by gavage in olive oil solution, at a dose of 46 mg/animal/week for 30 weeks. There were high incidences of hepatocellular carcinomas and cholangiocarcinomas in the liver and of squamous cell carcinomas and alveolar cell adenocarcinomas in the lung. In contrast with the activity of the next higher homolog, nitrosomethyldodecylamine, no bladder tumors were induced.


How to design virus containment policies? A joint analysis of economic and epidemic dynamics under the COVID-19 pandemic.
We analyze the impact of different designs of COVID-19-related lockdown policies on economic loss and mortality using a micro-level simulation model, which combines a multi-sectoral closed economy with an epidemic transmission model. In particular, the model captures explicitly the (stochastic) effect of interactions between heterogeneous agents during different economic activities on virus transmissions. The empirical validity of the model is established using data on economic and pandemic dynamics in Germany in the first 6 months after the COVID-19 outbreak. We show that a policy-inducing switch between a strict lockdown and a full opening-up of economic activity based on a high incidence threshold is strictly dominated by alternative policies, which are based on a low incidence threshold combined with a light lockdown with weak restrictions of economic activity or even a continuous weak lockdown. Furthermore, also the ex ante variance of the economic loss suffered during the pandemic is substantially lower under these policies. Keeping the other policy parameters fixed, a variation of the consumption restrictions during the lockdown induces a trade-off between GDP loss and mortality. Furthermore, we study the robustness of these findings with respect to alternative pandemic scenarios and examine the optimal timing of lifting containment measures in light of a vaccination rollout in the population.


Longitudinal changes in body mass index Z-scores during infancy and risk of childhood allergies.
Few studies address the dynamic changes of body mass index (BMI) Z-scores during infancy with breastfeeding and their impact on childhood atopic diseases. A total of 183 children from a birth cohort regularly followed-up for 4 years were enrolled in this study. Time series data of BMI Z-scores from 1 month to 2 years of age was clustered using K-means method in R software. Breastfeeding status during the first 6 months of life was recorded and classified. The total serum and specific immunoglobulin E (IgE) levels to food and inhalant allergens were measured at age 0.5, 1, 1.5, and 2 years. Using K-means clustering, the dynamic changes in BMI Z-scores were classified into three clusters (cluster A, increasing, n = 62; cluster B; decreasing, n = 62; cluster C, constant low, n = 59). Despite having no statistical association with atopic diseases, a decreasing trend in infantile BMI Z-scores was significantly associated with a higher prevalence of IgE sensitization at age 1 which increased the risk of rhinitis development at age 4 (P = 0.007). No difference in BMI Z-scores was determined between different breastfeeding patterns. However, exclusive formula feeding ≥6 months was found to be significantly associated with mite sensitization at age 1.5 years which risks asthma development at age 4 (P = 0.001). A decreasing trend of BMI Z-scores during infancy is determined to be inversely associated with IgE and allergen sensitization, which may potentially increase the risk of allergies in early childhood.


Effect of oxidized regenerated cellulose on the healing of pharyngeal wound: an experimental animal study.
This study aimed to investigate the relationship between oxidized regenerated cellulose (ORC) and mucosa healing in an experimental animal model. Fifteen adult Sprague-Dawley rats were randomly divided into three groups that underwent different wound treatments. In Group 1, no pharyngeal wound was created. In Group 2, the pharyngeal wound was sutured with Prolene only. In Group 3, the pharyngeal wound was sutured with Prolene, and covered with one layer of ORC before closure of the skin wound. The animals were euthanized either 5 or 10 days after operation, and wound conditions were inspected and recorded. Specimens including sections of larynx and pharynx/upper esophagus were taken for microscopic and molecular biological examination. The pharyngotomy/esophagotomy wounds achieved good healing outcomes 10 days after operation. Wounds treated with ORC had significantly diminished inflammatory cell infiltration in microscopic examination when compared with that of those without ORC 5 days after operation. The matrix metalloproteinases (MMP) expression level was higher in wounds of Group 2 and Group 3, when compared with that of group 1. In addition, the MMP expression level was lower in the ORC-treated wounds when compared with that of those without ORC. There was no significant difference in fibroblast proliferation, collagen deposition, endothelin-1, alpha-smooth muscle actin, and transforming growth factor beta 1 expression level between wounds treated with ORC and those without ORC. Reduced inflammatory response and decreased MMP expression level was observed in ORC-treated wounds. Whether ORC facilitates mucosa healing requires further investigation.


Subthalamic Nucleus Stimulation Does Not Have Any Acute Effects on Verbal Fluency or on Speed of Word Generation in Parkinson's Disease.
Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been shown to be generally safe from a cognitive perspective, with consistent evidence that the major impact of STN-DBS in Parkinson's disease (PD) is on verbal fluency. The aim of this study was first to identify the influence of acute manipulation of STN-DBS in PD on the number and time pattern of word generation on different verbal fluency (VF) tasks, phonemic, switching, and cued switching, and second to determine whether cueing improved VF and if cueing effects interacted with STN-DBS effects. Parallel versions of these three verbal fluency tasks were completed by 31 patients with Parkinson's disease who had had bilateral DBS of the STN, twice, with DBS On and Off, with the order counterbalanced across patients. There was no effect of acute STN-DBS on the total number of words generated during verbal fluency. As expected, the number of words generated significantly declined over the six 10-second intervals of the verbal fluency tasks, but this time pattern of word generation was not altered by STN-DBS. External cueing significantly increased the number of words generated relative to an uncued switching verbal fluency task, but the cueing effect on VF was not altered by STN-DBS. In conclusion, (i) acute STN-DBS manipulation did not alter either verbal fluency performance or the time pattern of word generation and (ii) external cueing significantly improved verbal fluency performance both with STN-DBS On and Off.


Modulation of human checkpoint kinase Chk1 by the regulatory beta-subunit of protein kinase CK2.
Protein kinase CK2 is a serine/threonine protein kinase involved in various aspects of cellular regulation. The regulatory beta-subunit of CK2 exerts a central role not only in mediating formation of tetrameric CK2 complexes but also as a docking partner for several protein kinases. In this study, CK2beta is found to interact with the human cell cycle checkpoint kinase Chk1. The Chk1-interacting region of CK2beta is localized at the C-terminus and the complex between CK2beta and Chk1 is devoid of the catalytic CK2alpha-subunit. The interaction between CK2beta and Chk1 leads to an increase in the Cdc25C phosphorylation activity of Chk1. The screening of several cell lines has revealed that the association between CK2beta and Chk1 also occurs in vivo at a different degree. Collectively, these studies confirm the implication of the regulatory beta-subunit of protein kinase CK2 in cell cycle regulation and identify a novel mechanism for the activation of Chk1 protein kinase.


Application of humic acid and hydroxyapatite in Cd-contaminated alkaline maize cropland: A field trial.
Soil quality is critical to the quality and safety of agricultural products, and remediation of heavy metal contaminated soils is an urgent task to be implemented. This study applied hydroxyapatite (HAP) and humic acid (HA) as remediation materials to Cd-contaminated alkaline cropland. Data on soil pH, electrical conductivity (EC), cation exchange capacity (CEC), soil organic matter (SOM), diethylenetriamine pentaacetic acid (DTPA) extraction, and improved BCR sequential extraction were obtained for different periods. The joint application of HAP and HA enhanced the soil's buffering capacity. During the experiment, treatment groups CK, H1, H2, H3, and H4 showed changes in pH of 0.29, 0.28, 0.21, 0.24, and 0.32, respectively, and changes in the conductivity of 341.4, 183.0, 133.1, 104.6 and 320.2 μS/cm. Soil organic matter had a positive effect on soil's effective phosphorus content. HAP and HA both reduced the BCFgrain/soil of Cd for the maize, but the impact of HA was more substantial (20.19 % reduction compared to CK). HA increased the yield of maize by 44.20 %. The combination of HA and HAP was recommended.


The accessory coracobrachialis muscle: ultrasound and MR features.
To present the prevalence, clinical relevance, and ultrasound (US) and magnetic resonance imaging (MRI) appearances of the accessory coracobrachialis (ACB) muscle. We present an US prospective study of the ACB muscle over a 2-year period. Five of the eight patients with suspected ACB on US were subsequently examined by MRI. An ACB muscle was demonstrated by US in eight patients (eight shoulders), including seven females, one male, with mean age 39 years, over 770 (664 patients) consecutive shoulder US examinations referred to our institution yielding a prevalence of 1.04%. In dynamic US assessment, one case of subcoracoid impingement secondary to a bulky ACB was diagnosed. No thoracic outlet syndrome was encountered in the remaining cases. MRI confirmed the presence of the accessory muscle in five cases. ACB muscle is a rarely reported yet not uncommon anatomic variation of the shoulder musculature encountered only in eight of 664 patients referred for shoulder US study. Its US and MRI appearance is described. One of our patients presented with subcoracoid impingement related to the presence of an ACB.


1H magnetic resonance spectroscopy study of thalamus in treatment resistant depressive patients.
Treatment-resistant depression (TRD) is a common clinical problem, and represents a considerable challenge to treatment, however, the pathogenesis of this disease is poorly understood. Thalamus is generally believed to have a role in the pathophysiology of depression. In this study, we adopted 1.5T (1)H magnetic resonance spectroscopy ((1)H MRS) to examine possible alterations of thalamus metabolism in 20 adult TRD patients. Our results suggested there might be damage and loss of neurons, as well as membrane phospholipids associated metabolism abnormality in the TRD thalamus.


Adolescents as Agents of Parental Healthy Lifestyle Behavior Change: COPE Healthy Lifestyles TEEN Program.
Obesity is a leading health crisis around the world. An intervention strategy scarcely utilized for behavior change is that of a child as change agent. The purpose of this study was to describe the impact of teens reviewing newsletters from a healthy lifestyle intervention with their parents. Evaluation data from a randomized controlled trial, COPE Healthy Lifestyle TEEN Program, was analyzed. A descriptive study was conducted of parents' and teens' lifestyle behaviors as reported by parents. One hundred sixty-nine parents completed evaluations. Two thirds of parents reported changing a behavior as a result of the program. Nearly three quarters of parents reported behavior changes in their teens. Over 90% reported they would recommend this or a similar program. The obesity epidemic shows no signs of reversal, and hence multiple approaches to impact healthy lifestyles are urgent. Including children as a change agent is a potential target for interventions addressing obesity.


Genistein potentiates Centchroman induced antineoplasticity in breast cancer via PI3K/Akt deactivation and ROS dependent induction of apoptosis.
Recently, strategies of cancer treatment using combination of agents with distinct molecular mechanism(s) of action are considered more promising due to its high efficacy and reduced systemic toxicity. The study is aimed to improve the efficacy of selective estrogen receptor modulator, Centchroman (CC) by combination with the phytoestrogen Genistein (GN). Cytotoxicity was evaluated by Sulforhodamine B assay. Cell cycle analysis was done through flow cytometry. Further, Apoptosis was analyzed using Annexin V/PI staining, tunel assay and electron microscopic examination and verified using western blot analysis. In order to validate the in vitro results, in vivo analysis was performed using 4T1-syngeneic mouse model. In this study, we report that the dietary isoflavone genistein (GN) synergistically improved antineoplasticity of CC in breast cancer by arresting cells at G2/M phase culminating in ROS dependent apoptosis. The combination of CC plus GN caused dysregulation of Bax and Bcl-2 ratio inducing mitochondrial dysfunction, activation of Caspase-3/7, -9 and PARP cleavage. Further, combination significantly suppresses phosphorylation of PI3K/Akt/NF-κB, enhancing apoptosis. Additionally, combination markedly reduced tumor growth compared to CC and GN alone in mouse 4T1 breast tumor model. Together, these studies suggest that GN represents a potential adjunct molecule whose role in CC induced apoptosis deserves attention.


Outcome of Gleason 3 + 5 = 8 Prostate Cancer Diagnosed on Needle Biopsy: Prognostic Comparison with Gleason 4 + 4 = 8.
ISUP (International Society for Urologic Pathology) and WHO adopted prognostic Grade Groups 1 to 5 that simplify prostate cancer grading for prognosis. Grade Group 4 is Gleason score 8 cancer, which is heterogeneous, and it encompasses Gleason score 4 + 4 = 8, 3 + 5 = 8 and 5 + 3 = 8. The comparative prognostic implications of these various Gleason scores had not been studied by urological pathologists after a re-review of slides. Patients with a highest biopsy Gleason score of 3 + 5 = 8 or 4 + 4 = 8 were included in the study. Controls were cases with a highest Gleason score of 4 + 3 = 7 or 9-10. A total of 423 prostatic biopsy cases accessioned from 2005 to 2013 at 2 institutions were reviewed. Clinicopathological findings and followup (median 33.4 months) were assessed. Among Gleason score 8 cancers the cancer status outcome in 51 men with Gleason score 3 + 5 = 8 was marginally worse than in 114 with Gleason score 4 + 4 = 8 (p = 0.04). This was driven by a persistent nonmetastatic (after radiation/hormone therapy) cancer rate of 37% among Gleason score 3 + 5 = 8 cases vs 24% among Gleason score 4 + 4 = 8 cases. Conversely, cancer specific survival at 36-month followup was 97.8% in 3 + 5 cases vs 92.6% in 4 + 4 cases but this was not significant (p = 0.089). Cancer specific survival in the Gleason score 8 group was dichotomized by the presence of cribriform growth (p = 0.018). All Gleason score categories did not differ in the fraction of biopsy cores positive, clinical presentation or pathological findings, including the frequency of Gleason pattern 5, in 70 patients who underwent prostatectomy. Using the most current standards of prostate cancer grading the prognosis is not different in Gleason score 3 + 5 = 8 and 4 + 4 = 8 cancers. This justifies including both in Grade Group 4.


[Anastomosis between carotis externa and carotis interna circulation (indication and results) (author's transl)].
An extra-intracranial anastomosis operation was carried out in 60 stroke patients in order to bypass the occlusion or severe stenosis in the internal carotid or middle cerebral artery. Postoperative angiographical follow-up studies showed a well functioning extra-intracranial bypass in more than 90 % of the patients. In many cases repeat angiography done weeks or months following surgery revealed an enlargement of the caliber of the extracranial artery used for constructing the bypass and also of the cerebral arteries that were irrigated by the bypass. Furthermore we noted that the new collateral channel was able to fill a steadely increasing part of the cerebral circulation and that it was also found to irrigate territories of the brain that were previously well perfused by leptomeningeal anastomosis or retrograd flow through the ophthalmic artery etc. resulting in a reversal of the direction of blood flow in these collaterals. The neurological follow-up examinations revealed that the increase in cerebral blood supply following the extra-intracranial anastomosis operation resulted in a considerable improvement of the post-stroke neurological deficits.


Spontaneous carotid-cavernous fistula with fibromuscular dysplasia.
A young woman presented with a spontaneous carotid-cavernous fistula. She also had fibromuscular dysplasia of the extracranial cerebral arteries. The possible relationship of the two diseases brought up important questions concerning how to manage the patient. Treatment by obliteration of the carotid circulation on one side would be expected to increase blood flow on the other side. If the cavernous carotid artery on the second side was weakened by fibromuscular dysplasia, the increased flow might predispose to the formation of a second carotid-cavernous fistula. We first attempted to avoid surgery. When progressive symptoms occurred, the cavernous sinus was obliterated with bronze wire, thus preventing venous shunting.