A global view of hepatocellular carcinoma: trends, risk, prevention and management.
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.


[25 years of the DRG-based health-financing system in Hungary].
After a thourough development phase, a new system of health financing was introduced in Hungary in 1993. One of the cornerstones of the system was the financing of acute hospital care through Diagnosis-Related Groups (DRGs). This method was part of a comprehensive healthcare model, elaborated and published around 1990 by experts of Gyógyinfok, a public institute. The health financing system that was finally introduced reflcted in large part this theoretical model, while the current Hungarian system differs from it in some important respects. The objective of this article is to identify these points of divergence.


Heavy metals exposure levels and their correlation with different clinical forms of fetal growth restriction.
Prenatal heavy metals exposure has shown a negative impact on birth weight. However, their influence on different clinical forms of fetal smallness was never assessed. To investigate whether there is a differential association between heavy metals exposure and fetal smallness subclassification into intrauterine growth restriction (IUGR) and small-for-gestational age (SGA). In this prospective case-control study, we included 178 mother-infant pairs; 96 of appropriate for gestational age (AGA) and 82 of small fetuses diagnosed in third trimester. The small ones were further subclassified into IUGR, n = 49 and SGA, n = 33. Cadmium (Cd), mercury (Hg), lead (Pb), arsenic (As) and zinc (Zn) levels were measured in the maternal and cord serum, and in the placentas of the three groups. Maternal serum level of Cd (p<0.001) was higher in the small fetuses compared to AGA. Fetal serum level of Cd (p<0.001) was increased in the small fetuses compared to AGA. Fetal serum level of Hg (p<0.05) showed an increase in SGA compared to both IUGR and AGA. Fetal serum level of Zn was increased in the AGA (p < 0.001) compared to each of the small fetuses groups. Only differences in the levels between the small fetuses' subgroups were detected in the fetal serum levels of Cd and Hg. Fetal birth weight was negatively correlated with the fetal serum level of Cd (p < 0.001). No differences in the placental heavy metal levels were observed among the groups. Fetal serum levels of Cd showed differential correlation between small fetuses' clinical subclassification, which together with the increased Cd levels in both maternal and fetal serum of the small fetuses reinforce the negative influence of heavy metals on birth weight. These findings provide more opportunities to verify the role of heavy metals exposure in relation to small fetuses' subclassification.


Molecular Pathways and Mechanisms of BRAF in Cancer Therapy.
With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF-mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/MAPK pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.


The dawn of dentistry in the late upper Paleolithic: An early case of pathological intervention at Riparo Fredian.
Early evidence for the treatment of dental pathology is found primarily among food-producing societies associated with high levels of oral pathology. However, some Late Pleistocene hunter-gatherers show extensive oral pathology, suggesting that experimentation with therapeutic dental interventions may have greater antiquity. Here, we report the second earliest probable evidence for dentistry in a Late Upper Paleolithic hunter-gatherer recovered from Riparo Fredian (Tuscany, Italy). The Fredian 5 human consists of an associated maxillary anterior dentition with antemortem exposure of both upper first incisor (I1 ) pulp chambers. The pulp chambers present probable antemortem modifications that warrant in-depth analyses and direct dating. Scanning electron microscopy, microCT and residue analyses were used to investigate the purported modifications of external and internal surfaces of each I1 . The direct date places Fredian 5 between 13,000 and 12,740 calendar years ago. Both pulp chambers were circumferentially enlarged prior to the death of this individual. Occlusal dentine flaking on the margin of the cavities and striations on their internal aspects suggest anthropic manipulation. Residue analyses revealed a conglomerate of bitumen, vegetal fibers, and probable hairs adherent to the internal walls of the cavities. The results are consistent with tool-assisted manipulation to remove necrotic or infected pulp in vivo and the subsequent use of a composite, organic filling. Fredian 5 confirms the practice of dentistry-specifically, a pathology-induced intervention-among Late Pleistocene hunter-gatherers. As such, it appears that fundamental perceptions of biomedical knowledge and practice were in place long before the socioeconomic changes associated with the transition to food production in the Neolithic.


The role of gesture delay in coda /r/ weakening: An articulatory, auditory and acoustic study.
The cross-linguistic tendency of coda consonants to weaken, vocalize, or be deleted is shown to have a phonetic basis, resulting from gesture reduction, or variation in gesture timing. This study investigates the effects of the timing of the anterior tongue gesture for coda /r/ on acoustics and perceived strength of rhoticity, making use of two sociolects of Central Scotland (working- and middle-class) where coda /r/ is weakening and strengthening, respectively. Previous articulatory analysis revealed a strong tendency for these sociolects to use different coda /r/ tongue configurations-working- and middle-class speakers tend to use tip/front raised and bunched variants, respectively; however, this finding does not explain working-class /r/ weakening. A correlational analysis in the current study showed a robust relationship between anterior lingual gesture timing, F3, and percept of rhoticity. A linear mixed effects regression analysis showed that both speaker social class and linguistic factors (word structure and the checked/unchecked status of the prerhotic vowel) had significant effects on tongue gesture timing and formant values. This study provides further evidence that gesture delay can be a phonetic mechanism for coda rhotic weakening and apparent loss, but social class emerges as the dominant factor driving lingual gesture timing variation.


Transfusion medicine and surgery.
Mortality after surgery in patients with severe and progressive anemia is an entity': risks related to blood loss and insufficient oxygen delivery to tissues are still a major concern in surgery. Risks of blood transfusion parallel those of blood loss: blood-borne infectious diseases and immunological side effects' may frustrate therapeutic efforts of surgery. Thus, blood transfusion in surgery must be kept to a level in which both risks are reduced to a minimum (or theoretically even absent). This review will deal with two relevant questions: (a) how to define the lowest amount of blood tranifusion needed for sur8ery and (b) how to reduce or abolish post-tranifusion risks of this amount.


Meta-analysis of associating liver partition with portal vein ligation and portal vein occlusion for two-stage hepatectomy.
Discussion is ongoing regarding whether associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) or portal vein occlusion is better in staged hepatectomy. The aim of this study was to compare available strategies using a two-stage approach in extended hepatectomy. A literature search was performed in MEDLINE, Scopus, the Cochrane Library and Embase, and additional articles were identified by hand searching. Data from the international ALPPS registry were extracted. Clinical studies reporting volumetric changes, mortality, morbidity, feasibility of the second stage and tumour-free resection margins (R0) in two-stage hepatectomy were included. Ninety studies involving 4352 patients, including 320 from the ALPPS registry, met the inclusion criteria. Among these, nine studies (357 patients) reported on comparisons with other strategies. In the comparison of ALPPS versus portal vein embolization (PVE), ALPPS was associated with a greater increase in the future liver remnant (76 versus 37 per cent; P < 0·001) and more frequent completion of stage 2 (100 versus 77 per cent; P < 0·001). Compared with PVE, ALPPS had a trend towards higher morbidity (73 versus 59 per cent; P = 0·16) and mortality (14 versus 7 per cent; P = 0·19) after stage 2. In the non-comparative studies, complication rates were 39 per cent in the PVE group, 47 per cent in the portal vein ligation (PVL) group and 70 per cent in the ALPPS group. After stage 2, mortality rates were 5, 7 and 12 per cent respectively. ALPPS is associated with greater future liver remnant hypertrophy and a higher rate of completion of stage 2, but this may be at the price of greater morbidity and mortality.


Consumer perceptions of beef healthiness: results from a qualitative study in four European countries.
Consumer perception of the healthiness of beef is an important determinant of beef consumption. However, little is known about how consumers perceive the healthiness of beef. The aim of this study is to shed light on the associations between beef and health. Eight focus group discussions were conducted in four European countries (France, UK, Germany, Spain), each consisting of seven to nine participants. A content analysis was performed on the transcripts of these discussions. Although beef was generally perceived as healthful, focus group participants expected positive as well as negative effects of beef consumption on their health. Labelled, branded, fresh and lean beef were perceived as signalling healthful beef, in contrast with further processed and packaged beef. Consumers felt that their individual choices could make a difference with respect to the healthiness of beef consumed. Focus group participants were not in favour of improving beef healthiness during processing, but rather focussed on appropriate consumption behaviour and preparation methods. The individual responsibility for health implies that consumers should be able to make correct judgements about how healthful their food is. However, the results of this study indicate that an accurate assessment of beef healthiness is not always straightforward. The presented results on consumer perceptions of beef healthiness provide insights into consumer decision making processes, which are important for the innovation and product differentiation in the European beef sector, as well as for public health policy decisions related to meat consumption in general and beef consumption in particular.


Comparative Study of Delirium in Emergency and Consultation Liaison- A Tertiary Care Hospital Based Study in Northern India.
Delirium is an acute and often fluctuating disturbance in level of consciousness and thought process (cognition) that develops over a short period of time and is a significant change from previous level of functioning. Its prevalence increases with age, complexity of medical co- morbidities and number of medications prescribed. To compare the cause and severity of delirium in patients in emergency and consultation liaison psychiatry group. A cross-sectional, tertiary care hospital based study was conducted on the patients who presented with delirium from emergency department (50) and consultation-liaison psychiatry groups (50), over a period of one year. The diagnosis was made on the basis of DSM- 5 criteria. The Delirium Rating Scale (DRS-R-98) was applied to know the severity of delirium, cognitive and non-cognitive symptoms of delirium in patients. The results were subjected to appropriate statistical analysis. In emergency group, 42% patients had metabolic abnormalities, while in consultation-liaison, 38% patients had hyponatremia and hypokalemia and the difference was found to be statistically non-significant (p>0.05). In emergency group, 21(42%) patients were diagnosed as delirium due to other medical condition, followed by 13 (26%) and 8(16%) patients, who were diagnosed as delirium due to multiple aetiologies and substance intoxication each respectively. In only 33(66%) cases in consultation liaison group patients had delirium secondary to other medical conditions. As per DRS-R98 Scale, mean severity score was found to be statistically significant (p<0.05) in consultation liaison group as compared to emergency department group (p> 0.05). Delirium is multifactorial aetiological disease, with variable but preventable outcome. Approach should be aimed at finding the treatable causes to reduce morbidity and mortality.


Functional magnetic resonance imaging of the basal ganglia and cerebellum using a simple motor paradigm.
Activation of cortical and subcortical motor areas of the brain, including primary motor cortex, supplementary motor area, basal ganglia and cerebellum, were successfully investigated in seven right-handed, normal volunteers during a simple, rapid, thumb flexion-extension task using functional magnetic resonance imaging. A multi-slice echo-planar imaging sequence was used to cover the entire brain. A signal increase varying from 2% to 6% was observed for the different regions involved in the motor task. Moving the non-dominant thumb was associated with a more bilateral activation pattern in both putamen and cerebellar regions. This study demonstrates the capability of functional magnetic resonance imaging to delineate simultaneously many activated brain areas that are commonly thought to be involved in the performance of motor tasks.


The role of the State Security Service (Stasi) in the context of international clinical trials conducted by western pharmaceutical companies in Eastern Germany (1961-1990).
After the building of the Berlin Wall in the 1960s, a number of international pharmaceutical manufacturers from the West had their drugs tested in Eastern Germany (GDR). So far, the extensive collection of documents on the subject stored in the archives of the GDR State Security Service (Stasi, MfS) has not been systematically analysed. Until now, the role of the Stasi with respect to the surveillance of the trials has been unclear. A keyword search within the database of the Stasi files was conducted. All available files were screened in order to identify institutions, companies and personnel involved in the clinical trials. On this basis, further files were requested. A total of 259 files were available for analysis. Relevant data was derived from 160 of these files. A contextualised approach was applied, which critically explored the origin, content, and impact of the data. In addition, an approach guided by the central steps of document analysis was applied. At least 400 clinical trials were conducted during the GDR period. The exact number remains speculative. According to references found in the Stasi files, it might have been considerably higher. Initially, the main goal of the trials was for the GDR authorities to decide whether to import certain Western drugs. By 1983, this intention had changed. Now, the primary aim of the trials was the procurement of foreign currency. The Stasi feared that the pharmaceutical companies could have a significant influence on GDR Health System. Stasi spies were holding positions in the responsible medical committees, universities, and hospitals. Constant surveillance by the Stasi served the purpose of monitoring any contact between people from the West and the East. Unknowingly, representatives of Western companies were surveilled by the Stasi. The studied documents also point to the fact that a number of clinical trials conducted during the GDR period did not comply with GDR regulations, and were therefore deemed illegal by the Stasi. The Stasi was not particularly interested in medico-ethical questions. Clinical trials conducted during the GDR period were surveilled by the Stasi. It was their aim to monitor all people involved in the trials, including their Western contacts. Relevant medico-ethical questions like patient consent and safety with respect to the clinical trials were not the focus. Considering the significant number of conducted trials, only limited evidence exists of doctors having discussed them critically. The public was not officially informed about the trials.


Reaction of hydrogen peroxide with ferrylhemoglobin: superoxide production and heme degradation.
The reaction of Fe(II) hemoglobin (Hb) but not Fe(III) hemoglobin (metHb) with hydrogen peroxide results in degradation of the heme moiety. The observation that heme degradation was inhibited by compounds, which react with ferrylHb such as sodium sulfide, and peroxidase substrates (ABTS and o-dianisidine), demonstrates that ferrylHb formation is required for heme degradation. A reaction involving hydrogen peroxide and ferrylHb was demonstrated by the finding that heme degradation was inihibited by the addition of catalase which removed hydrogen peroxide even after the maximal level of ferrylHb was reached. The reaction of hydrogen peroxide with ferrylHb to produce heme degradation products was shown by electron paramagnetic resonance to involve the one-electron oxidation of hydrogen peroxide to the oxygen free radical, superoxide. The inhibition by sodium sulfide of both superoxide production and the formation of fluorescent heme degradation products links superoxide production with heme degradation. The inability to produce heme degradation products by the reaction of metHb with hydrogen peroxide was explained by the fact that hydrogen peroxide reacting with oxoferrylHb undergoes a two-electron oxidation, producing oxygen instead of superoxide. This reaction does not produce heme degradation, but is responsible for the catalytic removal of hydrogen peroxide. The rapid consumption of hydrogen peroxide as a result of the metHb formed as an intermediate during the reaction of reduced hemoglobin with hydrogen peroxide was shown to limit the extent of heme degradation.


Cost and Quality Comparison of Hernia Surgery in Stationary, Day-Patient and Outpatient Care.
Medical progress is increasingly enabling more and more stationary treatment to be provided in the outpatient sector. This development should be welcomed, as healthcare costs have been rising for years. The design of efficient processes and a needs-based infrastructure enable further savings. According to international recommendations (EHS/IEHS), outpatient treatment of unilateral inguinal hernias is recommended. Data from patients in GZO Hospital Wetzikon/Zurich between 2019 and 2021 for unilateral inguinal hernia repair was included in this study (n = 234). Any over- or under-coverage correlated with one of the three treatment groups: stationary, partially stationary and patients treated in outpatients clinic. Complications and 30-day readmissions were also monitored. Final revenue for all patients is -95.36 CHF. For stationary treatments, the mean shifts down to -575.01 CHF, for partially stationary treatments the mean shifts up to -24.73 CHF, and for patients in outpatient clinic final revenue is 793.12 CHF. This result is also consistent with the operation times, which are lowest in the outpatient clinic with a mean of 36 min, significantly longer in the partially stationary setting with 58 min, and longest in the stationary setting with 76 min. The same applies to the anesthesia times and the relevant care times by the nurses as the most important cost factors in addition to the supply and allocation costs. We show that cost-effective elective unilateral inguinal hernia care in the outpatient clinic with profit (mean 793.12 CHF) is possible. Stationary unilateral hernia care (mean -575.01 CHF) is loss-making. Crucial factors for cost efficiency are optimized processes in the operating room (anesthesia, surgical technique and quality, operating time), as well as optimized care processes with minimal preoperative services and care times for the patient. However, at the same time, these optimizations pose a challenge to surgical and anesthesiology training and structures with high levels of preoperative and Postoperative services and pay-as-you-go costs. The complication rate is 0.91% lower than in a comparable study. The readmission within 30 days post-operation results with a positive deviation of -3.53% (stationary) and with a negative deviation of +2.29% (outpatient clinic) compared to a comparative study.


A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance.
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor that was clinically effective in a Phase III prevention trial. In vitro studies have shown that viral mutations conferring letermovir resistance map primarily to the UL56 component of the terminase complex and uncommonly to UL89. After serial culture of a baseline CMV laboratory strain under letermovir, mutation was observed in a third terminase component in 2 experiments, both resulting in amino acid substitution P91S in gene UL51 and adding to a pre-existing UL56 mutation. Recombinant phenotyping indicated that P91S alone conferred 2.1-fold increased letermovir resistance (EC50) over baseline, and when combined with UL56 mutation S229F or R369M, multiplied the level of resistance conferred by those mutations by 3.5-7.7-fold. Similarly a combination of UL56 mutations S229F, L254F and L257I selected in the same experiment conferred 54-fold increased letermovir EC50 over baseline, but 290-fold when combined with UL51 P91S. The P91S mutant was not perceptibly growth impaired. Although pUL51 is essential for normal function of the terminase complex, its biological significance is not well understood. Letermovir resistance mutations mapping to 3 separate genes, and their multiplier effect on the level of resistance, suggest that the terminase components interactively contribute to the structure of a letermovir antiviral target. The diagnostic importance of the UL51 P91S mutation arises from its potential to augment the letermovir resistance of some UL56 mutations at low fitness cost.


Clinical features of patients with hepatic portal venous gas.
Hepatic portal venous gas (HPVG) is a rare clinical condition that is caused by a variety of underlying diseases. However, the factors that would permit accurate identification of bowel ischemia, requiring surgery, in patients with HPVG have not been fully investigated. Thirty patients that had been diagnosed with HPVG using computed tomography between 2010 and 2019 were allocated to two groups on the basis of clinical and intraoperative findings: those with (Group 1; n = 12 [40%]) and without (Group 2; n = 18 [60%]) bowel ischemia. Eleven patients underwent emergency surgery, and bowel ischemia was identified in eight of these (73%). Four patients in Group 1 were diagnosed with bowel ischemia, but treated palliatively because of their general condition. We compared the characteristics and outcomes of Groups 1 and 2 and identified possible prognostic factors for bowel ischemia. At admission, patients in Group 1 more commonly showed the peritoneal irritation sign, had lower base excess, higher lactate, and higher C-reactive protein, and more frequently had comorbid intestinal pneumatosis. Of the eight bowel ischemia surgery patients, four (50%) died, mainly because of anastomotic leak following bowel resection and primary anastomosis (3/4, 75%). All except one patient in Group 2, who presented with aspiration pneumonia, responded better to treatment. Earlier identification and grading of bowel ischemia according to the findings at admission should benefit patients with HPVG by reducing the incidence of unnecessary surgery and increasing the use of safer procedures, such as prophylactic stoma placement.


Alcohol at bedtime induces minor changes in sleep stages and blood gases in stable chronic obstructive pulmonary disease.
The purpose of this study is to explore the effect of a moderate dose of alcohol on sleep architecture and respiration in chronic obstructive pulmonary disease (COPD). Alcohol depresses both hypercapnic and hypoxic ventilatory drives in awake, normal individuals and reduces the amount of rapid eye movement (REM) sleep and oxygen saturation (SpO2) in sleeping COPD subjects. Prospectively designed, open-label interventional study in a pulmonary rehabilitation hospital. Twenty-six (nine males) stable inpatients, median forced expiratory volume first second (FEV1) 40.5 % of predicted, median age 65 years, investigated by polysomnography including transcutaneous measurement of carbon dioxide pressure increase (ΔPtcCO2) in randomized order of either control sleep or intervention with 0.5 g of ethanol/kilogram bodyweight, taken orally immediately before lights off. Alcohol induced a mean increase (95 % confidence interval, [CI]) in the mean ΔPtcCO2 of 0.10 kPa (0.002-0.206, P = 0.047) and a mean decrease (CI) in the REM-sleep percentage of total sleep time (REM % of TST) of 3.1 % (0.2-6.0), (P = 0.020). Six subjects with apnea/hypopnea index (AHI) ≥15 had fewer apneas/hypopneas during alcohol versus control sleep (mean reduction of AHI 11 (1-20), P = 0.046). Alcohol-sleep changes in SpO2, but not in ΔPtcCO2, correlated with daytime arterial pressures of carbon dioxide (PaCO2) and oxygen (PaO2). Occasional use of a moderate, bedtime dose of alcohol has only minor respiratory depressant effects on the majority of COPD subjects, and in a minority even slightly improves respiration during sleep. However, caution is appropriate as this study is small and higher doses of alcohol may result in major respiratory depressive and additional negative health effects.


CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice.
Acute myeloid leukemia (AML) with mutated NPM1 shows distinctive biologic and clinical features, including absent/low CD34 expression, the significance of which remains unclear. Therefore, we analyzed CD34(+) cells from 41 NPM1-mutated AML. At flow cytometry, 31 of 41 samples contained less than 10% cells showing low intensity CD34 positivity and variable expression of CD38. Mutational analysis and/or Western blotting of purified CD34(+) cells from 17 patients revealed NPM1-mutated gene and/or protein in all. Immunohistochemistry of trephine bone marrow biopsies and/or flow cytometry proved CD34(+) leukemia cells from NPM1-mutated AML had aberrant nucleophosmin expression in cytoplasm. NPM1-mutated gene and/or protein was also confirmed in a CD34(+) subfraction exhibiting the phenotype (CD34(+)/CD38(-)/CD123(+)/CD33(+)/CD90(-)) of leukemic stem cells. When transplanted into immunocompromised mice, CD34(+) cells generated a leukemia recapitulating, both morphologically and immunohistochemically (aberrant cytoplasmic nucleophosmin, CD34 negativity), the original patient's disease. These results indicate that the CD34(+) fraction in NPM1-mutated AML belongs to the leukemic clone and contains NPM1-mutated cells exhibiting properties typical of leukemia-initiating cells. CD34(-) cells from few cases (2/15) also showed significant leukemia-initiating cell potential in immunocompromised mice. This study provides further evidence that NPM1 mutation is a founder genetic lesion and has potential implications for the cell-of-origin and targeted therapy of NPM1-mutated AML.


Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors.
New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.


Pericytes derived from the retinal microvasculature undergo calcification in vitro.
Pericytes isolated from the bovine retinal microvasculature retain characteristic features of their in vivo counterparts, such as the presence of glycogen deposits, long filamentous processes, prominent microfilament bundles and the ability to display two distinct and reversible phenotypes. Time-lapse video-microscopy demonstrated that pericytes tend to overlap and aggregate, even in sparse cultures. After reaching confluence, they form multilayered areas that retract away from each other, resulting in the formation of multicellular nodules. These nodules increase in size and cellularity by going through repeated 5- to 6-h cycles of anchoring, spreading, cell proliferation and retraction. Alkaline phosphatase was not detected in pericytes at subconfluent or confluent densities, but this enzyme was expressed in areas of high cell density, such as multilayers and nodules. Pericytes synthesise and deposit an extracellular matrix at all stages of their in vitro development, including nodule formation. The matrix within the nodules contains cross-striated collagen fibres and matrix vesicles. Needle-like crystals of hydroxyapatite appear to be deposited within the matrix, thus leading to massive calcification of the nodule. Calcification, as assessed by electron microscopy, histochemical staining and X-ray microprobe analysis, occurred on plastic and collagen substrate in the absence of disodium-beta-glycerophosphate. The addition of this compound at 5 or 10 mM or the use of a collagen substratum (rather than plastic), brought forward the process of nodule formation and calcification by 3-6 days. Our results suggest that retinal pericytes may differentiate in vitro along the osteogenic pathway.


Regarding the past, what is the trial you have always been dreaming of in CIDP?
Chronic inflammatory demyelinating polyradiculoneuropathy is an orphan disease of poorly understood cause. While first line treatments with corticosteroids, intravenous immunoglobulin and plasma exchange have at least short-term efficacy, no trial has shown that immunosuppressants work. In our dream, we will take advantage of the recently improved EU regulations to launch a Europe wide trial which will investigate the cause of the disease. It will compare three parallel groups, the anti-B cell agent rituximab, the anti-T cell agent abatacept and usual care. The trial will not be blinded and the design will be very simple. The primary outcome measure will be improvement from baseline of the overall neuropathy limitations scale (ONLS) score by 1 or more grades at 12 weeks without increase in concomitant corticosteroids or IVIg or use of plasma exchange. There will be an option to substitute improvement in the Rasch-built overall disability scale depending on future experience with that scale as the primary outcome measure. The trial will require 3 groups of 60 participants to detect an increase from 20% in the usual care group to 30% with one of the other agents with a power of 90% and P-value of 5%. It will be larger than any trial of an immunosuppressant agent so far performed in CIDP. However, recruitment will be easier because inclusion criteria will be broad and allow randomisation of any patient in whom their neurologist wishes to introduce an immunosuppressant. Avoidance of blinding and use of simple monitoring with facetime will simplify running the trial and reduce expense. The trial will follow participants and measure outcomes at 12 months. Other outcomes will consist only of grip strength, time to walk 10 m and Euroqol, the last allowing us to estimate the cost per QALY of rituximab or abatacept. Even including central analysis of key biomarkers, the trial will only cost 3 million euros, a fraction of the cost of the usual phase III pharmaceutical company trial.


Recognition memory for emotionally negative and neutral words: an ERP study.
Scalp recorded event-related potentials were used to investigate the neural activity elicited by emotionally negative and emotionally neutral words during the performance of a recognition memory task. Behaviourally, the principal difference between the two word classes was that the false alarm rate for negative items was approximately double that for the neutral words. Correct recognition of neutral words was associated with three topographically distinct ERP memory 'old/new' effects: an early, bilateral, frontal effect which is hypothesised to reflect familiarity-driven recognition memory; a subsequent left parietally distributed effect thought to reflect recollection of the prior study episode; and a late onsetting, right-frontally distributed effect held to be a reflection of post-retrieval monitoring. The old/new effects elicited by negative words were qualitatively indistinguishable from those elicited by neutral items and, in the case of the early frontal effect, of equivalent magnitude also. However, the left parietal effect for negative words was smaller in magnitude and shorter in duration than that elicited by neutral words, whereas the right frontal effect was not evident in the ERPs to negative items. These differences between neutral and negative words in the magnitude of the left parietal and right frontal effects were largely attributable to the increased positivity of the ERPs elicited by new negative items relative to the new neutral items. Together, the behavioural and ERP findings add weight to the view that emotionally valenced words influence recognition memory primarily by virtue of their high levels of 'semantic cohesion', which leads to a tendency for 'false recollection' of unstudied items.


ALK2/ALK3-BMPR2/ACVR2A Mediate BMP2-Induced Downregulation of Pentraxin 3 Expression in Human Granulosa-Lutein Cells.
Bone morphogenetic protein 2 (BMP2) belongs to the transforming growth factor-β superfamily and plays a critical role in regulating ovarian follicle function. Currently, the role of BMP2 during cumulus expansion remains to be determined. The aim of this study was to investigate the effect of BMP2 on the regulation of pentraxin 3 (PTX3) expression (the major component of cumulus expansion) and the underlying mechanisms in human granulosa-lutein (hGL) cells. Both primary and immortalized hGL cells were used as research models. Our results showed that treatment with BMP2 significantly suppressed the basal and luteinizing hormone-induced upregulation of PTX3. In addition, BMP2 stimulated the phosphorylation of SMAD1/5/8, and this effect was abolished by the addition of BMP type I receptor inhibitors, dorsomorphin homolog 1, and dorsomorphin but not SB431542. Moreover, the knockdown of activin receptorlike kinase 2/3 or BMP receptor type II/activin receptor type IIB receptors completely reversed the BMP2-induced phosphorylation of SMAD1/5/8 and restored PTX3 expression. Similarly, the knockdown of SMAD4 completely reversed the suppressive effect of BMP2 on the expression of PTX3. These results improve our understanding of the molecular mechanisms of BMP2 signaling. Our findings suggest that BMP2 may be involved in the regulation of cumulus expansion during the periovulatory stage.


The effect of beta-blockade on leg blood flow in hypertensive patients with intermittent claudication.
The present study was designed to assess the short-term effects of beta-blocking antihypertensive treatment on leg blood flow in patients with peripheral artery disease. Seven patients with intermittent claudication were randomly allocated to treatment with atenolol 100 mg or pindolol 10 mg. Patients switched therapy after one month of treatment. Venous occlusion plethysmography on the calves was used to assess the effects on leg blood flow after one and two months of treatment. The average 10% reduction of the systolic and diastolic blood pressures was not associated with any reduction of blood flow at rest. There was on average 3.4 ml reduction of peak flow which had no influence on the painfree or total walking distance.


Identification of inter-organ vascular network: vessels bridging between organs.
Development and homeostasis of organs and whole body is critically dependent on the circulatory system. In particular, the circulatory system, the railways shuttling oxygen and nutrients among various organs, is indispensible for inter-organ humoral communication. Since the modern view of the anatomy and mechanics of the circulatory system was established in 17(th) century, it has been assumed that humoral factors are carried to and from organs via vascular branches of the central arteries and veins running along the body axis. Over the past few decades, major advances have been made in understanding molecular and cellular mechanisms underlying the vascularization of organs. However, very little is known about how each organ is linked by vasculature (i.e., inter-organ vascular networks). In fact, the exact anatomy of inter-organ vascular networks has remained obscure. Herein, we report the identification of four distinct vessels, V1(LP), V2(LP), V3(LP) and V4(LP), that bridge between two organs, liver and pancreas in developing zebrafish. We found that these inter-organ vessels can be classified into two types: direct and indirect types. The direct type vessels are those that bridge between two organs via single distinct vessel, to which V1(LP) and V2(LP) vessels belong. The indirect type bridges between two organs via separate branches that emanate from a stem vessel, and V3(LP) and V4(LP) vessels belong to this type. Our finding of V1(LP), V2(LP), V3(LP) and V4(LP) vessels provides the proof of the existence of inter-organ vascular networks. These and other yet-to-be-discovered inter-organ vascular networks may facilitate the direct exchange of humoral factors that are necessary for the coordinated growth, differentiation and homeostasis of the connected organs. It is also possible that the inter-organ vessels serve as tracks for their connected organs to follow during their growth to establish their relative positions and size differences.


Gazing into space: Systematic biases in determining another's fixation distance from gaze vergence in upright and inverted faces.
The eyes of others play a crucial role in social interactions, providing information such as the focus of another's attention and their current thoughts and emotions. Although much research has focused on understanding how we perceive gaze direction, little has been done on gaze vergence, which can potentially yield information about the distance of another's fixation. Here, we presented participants with synthetic faces in a stereoscopically simulated 3-D environment to determine the absolute fixation distance at which they perceived a face to be gazing. The results showed an underestimation in fixation distance for downward-averted gaze and a limit in discrimination of gaze vergence beyond 35 cm. For inverted faces, fixation distance for gaze vergence in the lower visual field (corresponding to the avatar's upwards gaze) was underestimated, suggesting that our bias to underestimate others' fixation distance may rely on a viewer-centered, egocentric representation of interpersonal space.


Appetitive traits and child obesity: measurement, origins and implications for intervention.
Childhood obesity has multiple causes, most of them capable of explaining only one part of the problem. The population-wide impact of sedentary lifestyles and availability of energy-dense food is undeniable, but substantial individual differences in body weight persist, suggesting that individuals respond differently to the 'obesogenic' environment. One plausible mechanism for this variation is the early expression of appetitive traits, including low responsiveness to internal satiety signals, high responsiveness to external food cues, high subjective reward experienced when eating liked foods and preferences for energy-dense foods. Case-control studies support the existence of abnormalities in these traits among obese children compared with normal-weight children, and correlations between psychometric measures of child appetite and child weight suggest that appetitive trait profiles may not only promote obesity but also protect against it. The origins of appetitive traits are as yet uncharted, but will include both genetic and environmental influences. Parental feeding style may affect the development of appetite but the exact nature of the relevant behaviours is unclear and many studies are cross-sectional or begin late in childhood, obscuring causal relationships. Future research should explore determinants and biological mechanisms by using prospective designs beginning early in life, measuring relevant biomarkers such as gut hormones and incorporating neuroimaging and genotyping technologies. Potential clinical applications include the identification of 'at risk' children early in life and interventions to modify appetitive traits or ameliorate their impact on intake and weight.


Influence of string-like cooperative atomic motion on surface diffusion in the (110) interfacial region of crystalline Ni.
Although we often think about crystalline materials in terms of highly organized arrays of atoms, molecules, or even colloidal particles, many of the important properties of this diverse class of materials relating to their catalytic behavior, thermodynamic stability, and mechanical properties derive from the dynamics and thermodynamics of their interfacial regions, which we find they have a dynamics more like glass-forming (GF) liquids than crystals at elevated temperatures. This is a general problem arising in any attempt to model the properties of naturally occurring crystalline materials since many aspects of the dynamics of glass-forming liquids remain mysterious. We examine the nature of this phenomenon in the "simple" case of the (110) interface of crystalline Ni, based on a standard embedded-atom model potential, and we then quantify the collective dynamics in this interfacial region using newly developed methods for characterizing the cooperative dynamics of glass-forming liquids. As in our former studies of the interfacial dynamics of grain-boundaries and the interfacial dynamics of crystalline Ni nanoparticles (NPs), we find that the interface of bulk crystalline Ni exhibits all the characteristics of glass-forming materials, even at temperatures well below the equilibrium crystal melting temperature, Tm. This perspective offers a new approach to modeling and engineering the properties of crystalline materials.


Optimal substrate feeding policy for a fed batch fermentation with substrate and product inhibition kinetics.
The optimal substrate feeding policy for the fed batch fermentation which is governed by product and substrate inhibited kinetics is presented. The conjunction point between nonsingular and singular arcs and the feeding policy along the singular arc are derived analytically in terms of the concentrations of substrate and product and the liquid volume. Thus, it is possible to determine the feeding rate by monitoring the state variables (i.e., closed loop control). As a specific example, an optimization study of the fed batch fermentation for ethanol production by Saccharomyces cerevisiae is presented. It is shown that the optimal feeding patterns are heavily dependent upon the initial conditions. The point selectivity provides the guideline for predicting the optimal feeding patterns and explaining the results of rigorous mathematical analysis.


Risk Factors for Loss to Follow-up in 3202 Patients at 2 Years After Anterior Cruciate Ligament Reconstruction: Implications for Identifying Health Disparities in the MOON Prospective Cohort Study.
Understanding the risk factors for loss to follow-up in prospective clinical studies may allow for a targeted approach to minimizing follow-up bias and improving the generalizability of conclusions in anterior cruciate ligament reconstruction (ACLR) and other sports-related interventions. To identify independent risk factors associated with failure to complete (ie, loss to follow-up) patient-reported outcome measures (PROMs) at 2 years after ACLR within a well-funded prospective longitudinal cohort. Cohort study (prognosis); Level of evidence, 2. All patients undergoing primary or revision ACLR enrolled in the prospectively collected database of the multicenter consortium between 2002 and 2008 were included. Multivariate regression analyses were conducted to determine which baseline risk factors were significantly associated with loss to follow-up at a minimum of 2 years after surgery. Predictors assessed for loss to follow-up were as follows: consortium site, sex, race, marital status, smoking status, phone number provided (home or cell), email address provided (primary or secondary), years of school completed, average hours worked per week, working status (full-time, part-time, homemaker, retired, student, or disabled), number of people living at home, and preoperative PROMs (Knee injury and Osteoarthritis Outcome Score, Marx Activity Rating Scale, and International Knee Documentation Committee). A total of 3202 patients who underwent ACLR were enrolled. The 2-year PROM follow-up rate for this cohort was 88% (2821 of 3202). Multivariate analyses showed that patient sex (male: odds ratio [OR], 1.80) and race (black: OR, 3.64; other nonwhite: OR, 1.81) were independent predictors of 2-year loss to follow-up of PROMs. Education level was a nonconfounder. While education level did not predict loss to follow-up, patients who are male and nonwhite are at increased risk of loss to follow-up of PROM at 2 years. Capturing patient outcomes with minimal loss depends on equitable, not equal, opportunity to maximize generalizability and mitigate potential population-level health disparities. NCT00478894 (ClinicalTrials.gov identifier).


"Donor milk banking: Improving the future". A survey on the operation of the European donor human milk banks.
Provision of donor human milk is handled by established human milk banks that implement all required measures to ensure its safety and quality. Detailed human milk banking guidelines on a European level are currently lacking, while the information available on the actual practices followed by the European human milk banks, remains limited. The aim of this study was to collect detailed data on the actual milk banking practices across Europe with particular emphasis on the practices affecting the safety and quality of donor human milk. A web-based questionnaire was developed by the European Milk Bank Association (EMBA) Survey Group, for distribution to the European human milk banks. The questionnaire included 35 questions covering every step from donor recruitment to provision of donor human milk to each recipient. To assess the variation in practices, all responses were then analyzed for each country individually and for all human milk banks together. A total of 123 human milk banks completed the questionnaire, representing 85% of the European countries that have a milk bank. Both inter- and intra-country variation was documented for most milk banking practices. The highest variability was observed in pasteurization practices, storage and milk screening, both pre- and post-pasteurization. We show that there is a wide variability in milk banking practices across Europe, including practices that could further improve the efficacy of donor human milk banking. The findings of this study could serve as a tool for a global discussion on the efficacy and development of additional evidence-based guidelines that could further improve those practices.


[Fibromyalgia syndrome as a psychosomatic disorder - diagnosis and therapy according to current evidence-based guidelines].
The classification and therapy of patients with chronic widespread pain without evidence of somatic factors as an explanation is currently a matter of debate. The diagnostic label "fibromyalgia syndrome"(FMS) has been rejected by some representatives of general and psychosomatic medicine. A summary is given of the main recommendations from current evidence-based guidelines on FMS and nonspecific/functional/somatoform bodily complaints. The criteria of FMS and of persistent somatoform pain disorder or chronic pain disorder with somatic and psychological factors partly overlap. They include differential clinical characteristics of persons with chronic widespread pain but without sufficiently explaining somatic factors. Not all patients diagnosed with FMS meet the criteria of a persistent somatoform pain disorder. FMS is a functional disorder, in which in most patients psychosocial factors play an important role in both the etiology and course of illness. FMS can be diagnosed by looking at the history of a typical symptom cluster and excluding somatic differential diagnoses (without a tender point examination) using the modified 2010 diagnostic criteria of the American College of Rheumatology. Various levels of severity of FMS can be distinguished from a psychosomatic point of view, ranging from slight (single functional syndrome) to severe (meeting the criteria of multiple functional syndromes) forms of chronic pain disorder with somatic and psychological factors, of persistent somatoform pain disorder or of a somatization disorder. The diagnosis of FMS as a functional syndrome/stress-associated disorder should be explicitly communicated to the patient. A therapy within collaborative care adapted to the severity should be provided. For long-term management, nonpharmacological therapies such as aerobic exercise are recommended. In more severe cases, psychotherapy of comorbid mental disorders should be conducted. The coordinated recommendations of both guidelines can synthesize general medical, somatic, and psychosocial perspectives, and can promote graduated care of patients diagnosed with FMS.


ANMCO POSITION PAPER: Prognostic and therapeutic relevance of non-obstructive coronary atherosclerosis.
Atherosclerosis often affects the coronary arterial tree. Frequently the disease does not translate in significant narrowing of the vessels, thus determining only a non-obstructive disease. This condition that is described as non-obstructive coronary artery disease (NobsCAD) should be distinguished from the absence of disease (i.e. smooth coronary arteries) as it carries a specific prognostic value. The detection and reporting of NobsCAD should prompt preventive measures that can be individualized upon the degree of the underlying burden of disease. The accompanying clinical condition, the other cardiovascular risk factors present, and the description of the severity and extent of NobsCAD should provide the framework for an individualized treatment that should also consider the best available scientific evidence and guidelines. The description of NobsCAD represents important information to be collected whenever a coronary angiogram (both invasive and non-invasive) is performed. Treating the patient according to the presence and extent of NobsCAD offers prognostic benefits well beyond those offered by considering only the traditional cardiovascular risk factors. In order to reach this goal, NobsCAD should not be confused with the absence of coronary atherosclerosis or even ignored when detected as if it was a trivial information to provide.


The impact of MicroRNA-155 on the effect of cryoablation in paroxysmal atrial fibrillation.
Elevated plasma MicroRNA-155 (miR-155) levels are strongly associated with cardiac fibrosis and chronic inflammation processes. However, the relationship between miR-155 and paroxysmal atrial fibrillation (PAF) recurrence following cryoablation remains poorly explored. We aimed to evaluate whether elevated miR-155 is related to long-term AF recurrence following cryoablation. Preoperative miR-155 levels were determined in PAF patients undergoing initial cryoablation. Multivariate-adjusted Cox models were constructed to determine the relationship between miR-155 levels and PAF recurrence. Multivariate logistic regression analyses were performed to determine predictors of PAF recurrence. Of the 66 enrolled patients, 13 patients (19.7%) had recurrence at the 12-month following-up. These patients had significantly higher baseline miR-155 levels than those without PAF recurrence ((AAA ± BBB) vs. (AAA ± BBB), P < 0.05). The study results showed that miR-155 expression levels were significantly higher in the experimental group than in the control group. Additionally, logistic regression analysis revealed that miR-155 expression was positively correlated with PAF recurrence after cryoablation. Elevated preoperative miR-155 levels are related to a higher risk of AF recurrence and can independently predict AF recurrence following cryoablation.


Physical abuse in pregnancy.
Screening interviews to determine the extent of physical abuse were conducted for 742 women seen in the University of Virginia obstetric clinics. Eighty-one women (10.9%) reported that they had experienced abuse at some point in the past. These women were more likely to be divorced or separated, indigent, and less educated than were the non-abused control patients. They were more likely to have had emotional problems, and 20% had attempted suicide. Twenty-nine of the 81 women reported abuse during the current pregnancy, with 21% reporting increased abuse and 36% noting decreased abuse during pregnancy. Women living with an abusive partner did not experience a greater frequency of adverse pregnancy outcomes than did those who had left abusive relationships. An awareness of the extent of the problem and direct questioning will result in an increased identification of women who are at risk for physical abuse during pregnancy.


Identification of a major susceptibility locus for lethal graft-versus-host disease in MHC-matched mice.
Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Although it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility Ags and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was used in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F(1) mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. To identify the alleles responsible for GVHD susceptibility, a genome-scanning approach was taken using (B10.BR x BALB.K)F(1) x B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (logarithm of the odds, 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.


Why does the B3LYP hybrid functional fail for metals?
The B3LYP hybrid functional has shown to successfully predict a wide range of molecular properties. For periodic systems, however, the failure to attain the exact homogeneous electron gas limit as well as the semiempirical construction turns out to be a major drawback of the functional. We rigorously assess the B3LYP functional for solids through calculations of lattice parameters, bulk moduli, and thermochemical properties (atomization energies and reaction energies). The theoretical lattice constants overestimate the experimental ones by approximately 1%, and hence behave similarly to the PBE gradient-corrected exchange-correlation functional. B3LYP atomization energies of solids are drastically worse than those of nonempirical hybrid Hartree-Fock/density functionals (HF/DFT) such as PBE0 and HSE03. These large errors can be traced back to the lack of a proper description of "free-electron-like" systems with a significant itinerant character (metals and small gap semiconductors). Similar calculations using the popular semiempirical B3PW91 hybrid functional, which fulfills the uniform electron gas limit, show a clear improvement over B3LYP regarding atomization energies. Finally, theoretical values for heats of formation for both the B3LYP as well as the B3PW91 functionals are presented. These document a most likely fortuitously good agreement with experiment for the B3LYP hybrid functional.


Current status of soil-transmitted helminthiases among pre-school and school-aged children from Ile-Ife, Osun State, Nigeria.
A cross-sectional survey was conducted to determine the prevalence and intensity of soil-transmitted helminths among pre-school and school-aged children attending nursery and primary schools in Ile-Ife. Single stool samples were collected between January and March, 2009 from 352 children randomly selected from a total of 456 children attending both private and government schools. The stool samples were processed using the modified Kato-Katz technique, and then examined for the eggs of soil-transmitted helminths (STHs). One hundred and twenty-one (34.4%) samples were positive for STH eggs. The overall prevalences of Ascaris lumbricoides, Trichuris trichiura and hookworm were 33.2%, 3.7% and 0.9%, respectively. The prevalence of STH infection in government schools (47.8%) was significantly higher than in private schools (16.1%) (P < 0.001). The most common type of mixed infection was the combination of A. lumbricoides and T. trichiura (6.8%). The prevalence and intensity of A. lumbricoides rose with age. The lowest prevalence and intensity (7.7%; 0.240 ± 0.136 eggs per gram (epg)) were recorded in the 2- to 3-year-old age group, while the highest prevalence and intensity (58.7%; 1.820 ± 0.237 epg) were recorded in children aged 10 years and above. A questionnaire survey indicated that 73% of the children attending private school had been treated with anthelminthics less than 2 months prior to the collection of stool specimens, while 43% of the children attending government school received anthelminthic treatment during the same period. The findings indicate that STH infections are endemic among schoolchildren in Ile-Ife and that the burden of parasitic infections is greater in government schools than in private schools.


Some fundamental applications of the Law of La Place in Neurosurgery.
The Law of La Place is a simple principle of physics, applicable to any fluid-filled vessel, relating stress on the wall of the vessel to the radius and transmural pressure. This principle has major implications for neurosurgery and examples are provided relating La Place's Principle to the genesis and treatment of hydrocephalus, the surgical clipping of cerebral aneurysms and the technic of surgical sponge hemostatis.


Substrate registry in disordered layers of large molecules.
We present a statistic evaluation of the azimuth orientations of flat-adsorbed oligopyridine molecules in disordered adlayers on Au(111) and (111) oriented Ag-adlayers on Ru(0001). On both surfaces, we find a strong preference for a set of twelve angles, which belong to one specific, unsymmetrical alignment and its symmetry equivalents. These angles are also those that exclusively occur in more densely packed, ordered structures on the same surfaces. We describe a geometric fitting algorithm, which correctly predicts these angles, and which only requires the substrate lattice and the positions of the nitrogen atoms within the flat-adsorbed molecule as input parameters. Such predictions are particularly valuable to reduce the parameter space in structure simulations [C. Rohr, M. Balbás Gambra, K. Gruber, E. C. Constable, E. Frey, T. Franosch, B. A. Hermann, Nano Lett. 2009, 10, 833].


Temporal discounting does not influence body mass index.
The prevalence of obesity has driven searches for cognitive or behavioural economic factors related to Body Mass Index (BMI). One candidate is delay discounting: those who prefer smaller sooner rewards over larger but later rewards are hypothesised to have higher BMI. The findings in the literature are mixed however, with meta analyses suggesting only a very small correlation between discounting and BMI. Here we present novel empirical data (N=381) and Bayesian analyses which suggest no such relationship between discounting of either monetary or weight loss rewards and BMI. We also find evidence against our novel proposal that discounting moderates the rate of BMI gain over time. We also present our data in the context of a random effects Bayesian meta-analytical result which does suggest the presence of a small correlation overall. The strength of the correlation is so weak (2.25% shared variance) that its practical significance may be minor to non existent. However because we found decisive evidence for unaccounted for study-level variance, due to study heterogeneity, we argue that we should treat such meta-analytic correlations with extreme caution. While the relationship between discounting and health outcomes such as BMI remain theoretically appealing, our empirical and meta-analytic results suggest we should be cautious in inferring a correlational, let alone a causal, role for discounting processes in driving BMI or moderating BMI gain with age.


Cryphonectria radicalis: rediscovery of a lost fungus.
In an attempt to isolate the ascomycete Cryphonectria parasitica (Diaporthales, Valsaceae) from dead chestnut stems, we obtained three C. radicalis strains. All three strains were isolated in areas of Switzerland with high chestnut blight incidence. To confirm our species designation, we compared the three C. radicalis strains to hypovirus (hv)-free and hv-infected C. parasitica strains. The comparison revealed several distinctive characteristics. On potato dextrose agar in the dark, the C. radicalis strains produced a fluffy mycelium and small droplets of a purple exudate giving the mycelium a light pinkish appearance. On corn meal medium in the dark, the C. radicalis strains caused a color change of the medium to purple, whereas the C. parasitica strains did not cause any color change. Ascospores from C. radicalis were significantly smaller than C. parasitica ascospores and their dimensions fit within other published size ranges. Southern hybridization analysis of the two species using nuclear and mitochondrial probes support their taxonomic separation. This separation is further supported by the lack of successful interspecific crosses. In virulence tests on chestnut trees, the C. radicalis strains exhibited very low virulence, comparable to highly hypovirulent hv-infected C. parasitica strains. Our results suggest that C. radicalis still coexists with C. parasitica although at a low frequency.


Comparative efficacy and safety of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: a systematic review and network meta-analysis.
Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents. A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4+ cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4+ ≤/>200cells/μL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses). The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78-2.59) and NNRTIs (ORs 1.51-1.86), and similar but numerically higher than other INSTIs. CD4+ count increase was significantly greater with DTG than PIs (difference: 23.63-31.47 cells/μL) and efavirenz (difference: 34.54 cells/μL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76-100%) and NNRTIs (probability: 50-100%), and a greater CD4+ count increase versus PIs (probability: 72-100%) and NNRTIs (probability: 60-100%). DTG was more likely to result in patients achieving VS (probability: 94-100%), and a greater CD4+ count increase (probability: 53-100%) versus other core agents, including INSTIs (probability: 94-97% and 53-93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/μL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents. INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/μL, who can be difficult to treat.


Free skin grafting for treatment of distal limb skin defects in cats.
The technique and results of free skin grafts have been described in dogs, horses, rabbits, goats and mice. The procedure in cats is, however, described only indirectly in papers relating to dogs. A standard technique has been developed by the authors for use in cats, and is reported for 17 grafts in 16 cats with traumatic injury to the legs resulting in large areas of skin loss. This paper describes the preparation of the wound for grafting, the harvesting of the graft, graft placement, postoperative care and the results of the application of this technique. The success rate in this series of cases was high. This was attributed to proper preparation of the recipient site, collection of the graft and postoperative bandaging. The results suggest that the success rate of free skin grafts in cats is considerably higher than that achieved by the present authors in dogs, and reported for dogs by other surgeons in the literature.


Venous thromboembolism in malignancy and malignancy in venous thromboembolism.
The activation of coagulation in patients with cancer contributes significantly to morbidity and mortality rates and may play a fundamental role in the host response to growing tumours. Patients with cancer are clearly at high risk for the development of venous thromboembolism (VTE), particularly during chemotherapy and surgery. This situation is aggravated by the use of venous access catheters and possibly growth factors. Data derived from large, randomized, controlled trials have been used to determine the true incidence of this complication of cancer and its treatment. The incidence based on the analyses of these randomized controlled trials varies from 1% for limited stage patients with breast cancer treated with tamoxifen to 60% for patients with any type of cancer who are subjected to orthopaedic surgery and do not receive prophylactic therapy. In view of the morbidity and mortality attributable to VTE in cancer, widespread utilization of prophylactic anticoagulation therapy, which has proven safe and effective in a variety of situations, should be considered. While migratory thrombophlebitis is a clear indicator of an underlying neoplasm, the risk of cancer in patients with the more typical form of VTE has been the subject of intense debate over recent years. Some investigators have suggested that the relative risk of being diagnosed with an occult cancer within 6 months of an episode of VTE (particularly recurrent VTE) could be up to 10-fold. However, the cost-effectiveness of aggressive screening for cancer in patients with VTE has not yet been defined adequately.


TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFalpha. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wild-type adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.


Optimal Quadratic Binding for Relational Reasoning in Vector Symbolic Neural Architectures.
Binding operation is fundamental to many cognitive processes, such as cognitive map formation, relational reasoning, and language comprehension. In these processes, two different modalities, such as location and objects, events and their contextual cues, and words and their roles, need to be bound together, but little is known about the underlying neural mechanisms. Previous work has introduced a binding model based on quadratic functions of bound pairs, followed by vector summation of multiple pairs. Based on this framework, we address the following questions: Which classes of quadratic matrices are optimal for decoding relational structures? And what is the resultant accuracy? We introduce a new class of binding matrices based on a matrix representation of octonion algebra, an eight-dimensional extension of complex numbers. We show that these matrices enable a more accurate unbinding than previously known methods when a small number of pairs are present. Moreover, numerical optimization of a binding operator converges to this octonion binding. We also show that when there are a large number of bound pairs, however, a random quadratic binding performs, as well as the octonion and previously proposed binding methods. This study thus provides new insight into potential neural mechanisms of binding operations in the brain.


A proposal for cadaver organ procurement: routine removal with right of informed refusal.
In order to alleviate the shortage of vital organs for transplant, we propose a system of routine removal of cadaver organs with an option of informed refusal by family. Unless an individual registered an objection during his or her lifetime, or unless the family objected to the procedure, clinicians would be permitted routinely to salvage vital organs for transplant. Our proposal charts a middle path between the current ineffective policy based on "encouraged voluntarism" and "presumed consent" policies that promise effectiveness at the cost of violating traditional ethical and legal principles. In this article, we analyze the failure of the current regime, articulate a policy of routine removal subject to the right of informed refusal, and defend this policy against several possible objections.


Myelin basic protein inhibits the calcium response to phytohaemagglutinin in human lymphocytes.
Myelin Basic Protein, one of the major membrane protein component of the central nervous system, was used to probe the molecular mechanism of cellular activation by phytohaemagglutinin. Pre-treatment of human lymphocytes with myelin basic protein results in a lower rising of cytosolic concentration of free calcium after stimulation with phytohaemagglutinin. This effect is dependent on myelin basic protein concentration and on the preincubation time of the protein with the cells. It is not due to a interaction between myelin basic protein and phytohaemagglutinin, but appears to be a consequence of the binding of the protein to the cell surface. The reduction of the rise of cytosolic calcium induced by phytohaemagglutinin is specific for the myelin basic protein because other proteins like albumin and protamine have no effect.


Effectiveness and Safety of Systemic Therapy for Psoriasis in Older Adults: A Systematic Review.
Treating older adults with psoriasis can be challenging owing to comorbidities, concomitant medication use, and consequent safety risks. Although many studies focus on the effectiveness and safety of systemic antipsoriatic therapies in the general population, their effectiveness in older adults with psoriasis has not been systematically assessed. To evaluate the effectiveness and safety of systemic antipsoriatic therapies in patients 65 years or older. A systematic literature search was conducted in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) on November 11, 2019. No date limit was used. Randomized clinical trials, cohort studies, large case series, and meta-analyses assessing efficacy (or effectiveness) and/or safety of systemic antipsoriatic therapies in patients 65 years or older were included. The initial search yielded 11 096 results, of which 31 unique articles with 39 561 patients were included in analysis. Overall, limited data were available per systemic agent, and overall quality of the included studies on conventional systemic therapies was low. At the end of the induction phase (12-16 weeks after start of treatment), a reduction of 75% in Psoriasis Area and Severity Index was achieved in 49% of 74 methotrexate sodium users 65 years or older, 46% to 52.6% of 178 older cyclosporin users, 27% to 47.8% of 108 older acitretin users, 15.6% to 64% of 256 etanercept users 65 years or older, 66.7% to 93% of 43 infliximab users 65 years or older, 60.7% to 65% of 100 adalimumab users 65 years or older, 56.5% of 46 ustekinumab users 65 years or older, and 86.4% of 67 secukinumab users 65 years or older. Effectiveness of acitretin, etanercept, adalimumab, and secukinumab appeared not to be associated with age; studies regarding other systemic antipsoriatic therapies did not provide age group comparisons. Older age was significantly associated with renal function deterioration in cyclosporin users and with lymphopenia in fumaric acid esters users (hazard ratio, 2.42; 95% CI, 1.65-3.55; P < .001). Infections were the most frequently reported adverse event in patients 65 years or older using biologics, but no significant association with age was found. On the basis of limited available evidence, age alone should not be a limiting factor in psoriasis management. Awareness of comorbidities and concomitant medication use is very important, as well as appropriate dosing and frequent laboratory and clinical monitoring. More real-world evidence and (sub)analyses of prospective cohort studies on the effectiveness and safety of systemic therapies in older adults are critical to optimize personalized, effective, and safe antipsoriatic management in this growing patient group.


Vitamin D Daily versus Monthly Administration: Bone Turnover and Adipose Tissue Influences.
Vitamin D is involved in bone metabolism and in many various extra-skeletal diseases such as malabsorption syndromes, cardiovascular and metabolic diseases, cancer, and autoimmune and neurological diseases. However, data on the optimal route of administration are not consistent. The aims of our study were to analyze not only the influence of daily vs. monthly administration of vitamin D on bone metabolism and bone turnover, but also the effects of different routes of administration on fat mass in a cohort of adults with low levels of 25(OH) vitamin D3 at baseline. We analyzed 44 patients with hypovitaminosis at baseline and after six months of two different regimens of administration: seven drops (1750 IU)/day vs. 50,000 IU/month. We found that the two regimens were equivalent; 36 out of 44 patients reached the normal range of vitamin D after six months of treatment. Interestingly, the main determinant of vitamin D at baseline was the waist circumference. In addition, 22 patients treated by monthly regimen were evaluated after 18 months of treatment. At the end of follow-up, patients showed normal levels of vitamin D, with increased calcium levels and decreased bone turnover. Waist circumference also decreased. Our results support the efficacy of vitamin D3 given monthly both for correcting hypovitaminosis and for maintaining vitamin D levels. The relationship between serum 25(OH)vitamin D3 concentration and waist circumference supports vitamin D having a protective role in the current setting, since waist size is directly associated with the risk of cardiovascular and metabolic diseases.


Biochemical characterisation of chlorophyllase from leaves of selected Prunus species--a comparative study.
Despite senescence-induced chlorophyll depletion in plants has been widely studied, the enzymatic background of this physiologically regulated process still remains highly unclear. The purpose of this study was to determine selected biochemical properties of partially purified fractions of chlorophyllase (Chlase, chlorophyll chlorophyllido-hydrolase, EC 22.214.171.124) from leaves of three Prunus species: bird cherry (Prunus padus L.), European plum (Prunus domestica L.), and sour cherry (Prunus cerasus L.). Secondarily, this report was aimed at comparing seasonal dynamics of Chlase activity and chlorophyll a (Chl a) content within investigated plant systems. Molecular weight of native Chlase F1 has been estimated at 90 kDa (bird cherry) and approximately 100 kDa (European plum and sour cherry), whereas molecular mass of Chlase F2 varied from 35 kDa (European plum) to 60 kDa (sour cherry). Furthermore, enzyme fractions possessed similar optimal pH values ranging from 7.6 to 8.0. It was found that among a broad panel of tested metal ions, Hg(+2), Fe(+2), and Cu(+2) cations showed the most pronounced inhibitory effect on the activity of Chlase. In contrast, the presence of Mg(+2) ions influenced a subtle stimulation of the enzymatic activity. Importantly, although Chlase activity was negatively correlated with the amount of Chl a in leaves of examined Prunus species, detailed comparative analyses revealed an incidental decrement of enzymatic activity in early or moderately senescing leaves. It provides evidence that foliar Chlase is not the only enzyme involved in autumnal chlorophyll breakdown and further in-depth studies elucidating this catabolic process are required.


Systems biology strategy to study lipotoxicity and the metabolic syndrome.
Systems biology views and studies the biological systems in the context of complex interactions between their building blocks and processes. Given its multi-level complexity, metabolic syndrome (MetS) makes a strong case for adopting the systems biology approach. Despite many MetS traits being highly heritable, it is becoming evident that the genetic contribution to these traits is mediated via gene-gene and gene-environment interactions across several spatial and temporal scales, and that some of these traits such as lipotoxicity may even be a product of long-term dynamic changes of the underlying genetic and molecular networks. This presents several conceptual as well as methodological challenges and may demand a paradigm shift in how we study the undeniably strong genetic component of complex diseases such as MetS. The argument is made here that for adopting systems biology approaches to MetS an integrative framework is needed which glues the biological processes of MetS with specific physiological mechanisms and principles and that lipotoxicity is one such framework. The metabolic phenotypes, molecular and genetic networks can be modeled within the context of such integrative framework and the underlying physiology.


The effect of furosemide on intravascular volume status and electrolytes in patients receiving mannitol: an intraoperative safety analysis.
Mannitol is often used during intracranial surgery to improve surgical exposure. Furosemide is often added to mannitol to augment this effect. The concern exists, however, that the augmented diuresis caused by the addition of furosemide to mannitol may cause hypovolemia and hypoperfusion, hypokalemia, and hyponatremia. We examined the intraoperative safety of low-dose furosemide (0.3 mg/kg) combined with mannitol (1 g/kg). We observed 23 patients in a double-blind, block randomized, placebo-controlled study to examine the effects of furosemide (0.3 mg/kg) when combined with mannitol (1 g/kg) on surgical brain relaxation for tumor surgery. Mannitol and the study drug (furosemide or placebo) were administered, and arterial blood gases with electrolytes (sodium, potassium, and lactic acid) and urine output volume were recorded every 30 minutes for 3 hours. Plasma sodium, potassium, and lactic acid concentrations, and interval urine outputs, were compared across time and between furosemide-placebo assignment groupings, with a P<0.01 considered significant. Although mannitol produced a large volume of diuresis (1533±335 mL), the addition of a low dose of furosemide substantially increased both the rate of production of urine for the first 90 minutes after administration and the total volume of urine produced (2561±611 mL, P<0.001, compared with placebo group). The addition of furosemide did not produce a serum potassium level below 3.8±0.7 mEq/L, a serum sodium level below 128.3±3.4 mEq/L, or a serum lactic acid level above 2.4±0.9 mmol/L. There were no differences in the plasma potassium concentration, sodium concentration, or lactic acid concentration between the drug groups at any time point. Despite an increase in urine output by as much as 67%, adding low-dose furosemide to mannitol does not seem to produce significant electrolyte derangements or hypovolemia compared with the administration of mannitol alone.


Metabolism of the mutagen MeIQx in vivo: metabolite screening by liquid chromatography-thermospray mass spectrometry.
2-Amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx) is a potent mutagen found in cooked food. MeIQx and its isotopically labelled (13C, 15N2 and 14C) analogues were synthesised and used for metabolic studies in vivo. An equimolar mixture of MeIQx and its 13C, 15N2 stable isotope labelled analogue (containing tracer amounts of 14C-MeIQx) was given intraperitoneally to mice. Some 67% of the radioactivity was eliminated in urine and faeces within 24h. Four radiolabelled species were observed when urine was analysed by HPLC, corresponding to unchanged MeIQx and three more polar metabolites. Urine was analysed directly by HPLC-thermospray mass spectrometry. Four signals were observed containing the characteristic 1:1 isotopic doublet, corresponding to unchanged MeIQx, an MeIQx glucuronide, and two uncharacterized metabolites.


Multiple intestinal lipomatosis. Case report.
Intestinal lipomatosis is a rare disease with an incidence at autopsy ranging from 0.04 to 4.5%. Few cases have been reported in the medical literature. The condition is usually asymptomatic. Symptomatic cases usually present as obstruction or, less frequently, as bleeding. Intestinal barium studies, ultrasonography and computed tomography (CT) are useful diagnostic techniques. A 51-year-old male was evaluated for progressive abdominal pain, tachycardia, headache and nausea. One year before this examination, he was evaluated for gastrointestinal bleeding. Abdominal CT with contrast enhancement demonstrated multiple submucosal masses in stomach and small bowel. CT and barium examination features were typical of lipomas. No specific treatment, invasive procedures or surgery were performed for the asymptomatic intestinal lipomas. The patient has remained symptom-free for 1 year. Benign tumors of the small bowel are relatively rare, with lipoma being the most common type. The case reported here is considered to be unusual because stomach, duodenum, jejunum and ileum were affected. Lipomas are usually seen as smooth, nonulcerated filling defects. With these typical radiographic findings, preoperative diagnosis is possible keeping in mind this rare disease.


Plasma micro-RNA biomarkers for diagnosis and prognosis after traumatic brain injury: A pilot study.
Prediction of post-concussive syndrome after apparent mild traumatic brain injury (TBI) and subsequent cognitive recovery remains challenging, with substantial limitations of current methods of cognitive testing. This pilot study aimed to determine if levels of micro ribonucleic acids (RNAs) circulating in plasma are altered following TBI, and if changes to levels of such biomarkers over time could assist in determination of prognosis after TBI. Patients were enrolled after TBI on presentation to the Emergency Department and allocated to three groups: A - TBI (physical trauma to the head), witnessed loss of consciousness, amnesia, GCS=15, a normal CT Brain and a recorded first pass after post-traumatic amnesia (PTA) scale; B TBI, witnessed LOC, amnesia, GCS=15, a normal CT brain and a PTA scale test fail and: C - TBI and initial GCS <13 on arrival to the ED. Venous blood was collected at three time points (arrival, day 5 and day 30). Isolation of cell-free total RNA was then assayed using a custom miRNA PCR array. Two micro-RNAs, mir142-3p and mir423-3p demonstrated potential clinical utility differentiating patients after mild head injury into those at greater risk of developing amnesia and therefore, post-concussive syndromes. In addition, these miRNA demonstrated a decrease in expression over time, possibly indicative of brain healing after the injury. Further evaluation of these identified miRNA markers with larger patient cohorts, correlation with clinical symptoms and analysis over longer time periods are essential next steps in developing objective markers of severity of TBI.


Impact of our understanding of the genetic aetiology of epilepsy.
A genetic contribution to aetiology is estimated to be present in up to 40% of patients with epilepsy. It is useful to categorise genetic epilepsies according to the mechanisms of inheritance into Mendelian disorders, non-mendelian or 'complex' disorders, and chromosomal disorders. Over 200 Mendelian diseases include epilepsy as part of the phenotype, and the genes for a number of these have been identified recently. These include autosomal recessive progressive myoclonic epilepsies such as Unverricht-Lundborg disease, Lafora disease and the neuronal ceroid lipofuscinoses, and three autosomal dominant idiopathic epilepsies. The last named have been shown to arise from mutations in ion channel genes. Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in CHRNA4, benign familial neonatal convulsions by mutations in KCNQ2 and KCNQ3, and generalised epilepsy with febrile seizures plus by mutations in SCN1B. 'Complex', familial epilepsies are more difficult to analyse, but evidence has been obtained for loci predisposing to juvenile myoclonic epilepsy on chromosome 6p and 15q. Lastly, the genes underlying several spike-wave epilepsies in mice have been cloned, and three of these encode sub-units of voltage-gated calcium channels.


Phyllotactic regularity requires the Paf1 complex in Arabidopsis.
In plants, aerial organs are initiated at stereotyped intervals, both spatially (every 137° in a pattern called phyllotaxis) and temporally (at prescribed time intervals called plastochrons). To investigate the molecular basis of such regularity, mutants with altered architecture have been isolated. However, most of them only exhibit plastochron defects and/or produce a new, albeit equally reproducible, phyllotactic pattern. This leaves open the question of a molecular control of phyllotaxis regularity. Here, we show that phyllotaxis regularity depends on the function of VIP proteins, components of the RNA polymerase II-associated factor 1 complex (Paf1c). Divergence angles between successive organs along the stem exhibited increased variance in vip3-1 and vip3-2 compared with the wild type, in two different growth conditions. Similar results were obtained with the weak vip3-6 allele and in vip6, a mutant for another Paf1c subunit. Mathematical analysis confirmed that these defects could not be explained solely by plastochron defects. Instead, increased variance in phyllotaxis in vip3 was observed at the meristem and related to defects in spatial patterns of auxin activity. Thus, the regularity of spatial, auxin-dependent, patterning at the meristem requires Paf1c.


LDL-cholesterol target levels achievement in high-risk patients: An (un)expected gender bias.
Lowering low-density lipoprotein cholesterol (LDL-C) is the cornerstone of cardiovascular disease prevention. Collection of epidemiological data is crucial for monitoring healthcare appropriateness. This analysis aimed to evaluate the proportion of high-risk patients who achieved guidelines recommended LDL-C goal, and explore the predictors of therapeutic failure, with a focus on the role of gender. Health administrative and laboratory data from seven Local Health Districts in Tuscany were collected for residents aged ≥45 years with a history of major adverse cardiac or cerebrovascular event (MACCE) and/or type 2 diabetes mellitus (T2DM) from January 1, 2019, to January 1, 2021. The study aimed to assess the number of patients with optimal levels of LDL-C (<55 mg/dl for patients with MACCE and <70 mg/dl for patients with T2DM without MACCE). A cohort of 174 200 individuals (55% males) was analyzed and it was found that 11.6% of them achieved the target LDL-C levels. Female gender was identified as an independent predictor of LDL-C target underattainment in patients with MACCE with or without T2DM, after adjusting for age, cardiovascular risk factors, comorbidities, and district area (adjusted-IRR 0.58 ± 0.01; p < 0.001). This result was consistent in subjects without lipid-lowering therapies (adjusted-IRR 0.56 ± 0.01; p < 0.001). In an unselected cohort of high-risk individuals, females have a significantly lower probability of reaching LDL-C recommended targets. These results emphasize the need for action to implement education for clinicians and patients and to establish clinical care pathways for high-risk patients, with a special focus on women.


An international primary care survey of GERD terminology and guidelines.
Terminology used to describe upper gastrointestinal disorders differs by country and language. However, the extent of variation in physician understanding of GERD and associated conditions and symptoms is not known. To determine the knowledge of primary care physicians with regard to: terminology related to GERD, their understanding of related complications and extra-esophageal symptoms/conditions, and their use of guidelines relating to GERD. Gastroenterologists from 17 countries asked primary care physician colleagues to complete a one-page online survey on GERD. 352 primary care physicians, (77% community-based, 23% hospital-based) completed the questionnaire. Gastroesophageal reflux disease/GERD (84%) or reflux/reflux disease (47%) were the terms mostly often used to record a diagnosis for patients with reflux-related symptoms or clinical manifestations; dyspepsia (15%), epigastric pain (10%), and gastritis (9%) were infrequently used. Erosive esophagitis, Barrett's esophagus, stricture, and esophageal adenocarcinoma were recognized as being associated with GERD by 88, 71, 61 and 51% of physicians, respectively. Extra-esophageal problems of cough, sleep-related disorders, laryngitis and asthma were recognized to be associated with GERD by 74, 50, 48 and 47% of respondents. Thirty-nine percent of physicians stated that they did not use a specific definition of GERD; 33% used an international and 14% used a national guideline in managing patients. (1) GERD is well recognized, but its related terminology is variable throughout the world. (2) There was variable and incomplete recognition of extra-esophageal manifestations GERD. (3) Recognition of extra-esophageal diseases caused by GERD is variable. (4) Current GERD guidelines are infrequently used by primary care physicians.


[Dynamic psychiatric interpretation of a disease model of trichotillomania].
Every patient's "communal existence" allows to interpret deviations of behavior such as trichotillomania as a disturbance of interaction. When the child begins to wangle out of the dual union between mother and child it needs ways to delimitate itself, If the mother does not concede this demarcation (f. i. because she does not want to release the child from the symbiosis and therefore is "overprotecting") the child often becomes a victim of despair and, later on, of perplexity. At last it uses the own body as "Vis-a-vis". The accumulated aggressiveness is then worked off motorically by means of trichotillomania. In this way despair and perplexity in the field of interaction are passed on so to speak "atmospherically" to the mother, who in turn, having arranged treatment, transfers them on to the doctor. It is discussed how the area of irritation can be dissolved.