Culture of Small Barley Embryos on Defined Media.
Barley embryos, measuring 90 Fz in length, grew and became differentiated on a phosphate-enriched White's medium which was fortified with glutamine and alanine as major sources of organic nitrogen, and lesser amounts of five other amino acids. The pH of the medium was a critical factor in differentiation. On this medium, excised barley embryos developed more rapidly than embryos remaining in vivo, or embryos grown on media containing coconut milk.


Calibrating the response to health warnings: limiting both overreaction and underreaction with self-affirmation.
Self-affirmation, reflecting on one's defining personal values, increases acceptance of threatening information, but does it do so at the cost of inducing undue alarm in people at low risk of harm? We contrast an alarm model, wherein self-affirmation simply increases response to threat, with a calibration model, wherein self-affirmation increases sensitivity to the self-relevance of health-risk information. Female seafood consumers (N = 165) completed a values self-affirmation or control task before reading a U.S. Food and Drug Administration brochure on mercury in seafood. Findings support the calibration model: Among frequent seafood consumers, self-affirmation generally increased concern (reports of depth of thought, personal message relevance, perceived risk, and negative affect) for those high in defensiveness and reduced it for those low in defensiveness. Among infrequent consumers of seafood, self-affirmation typically reduced concern. Thus, self-affirmation increased the sensitivity with which women at different levels of risk, and at different levels of defensiveness, responded cognitively and affectively to the materials.


Mistrust in marriage--reasons why men do not accept couple HIV testing during antenatal care- a qualitative study in eastern Uganda.
A policy for couple HIV counseling and testing was introduced in 2006 in Uganda, urging pregnant women and their spouses to be HIV tested together during antenatal care (ANC). The policy aims to identify HIV-infected pregnant women to prevent mother-to-child transmission of HIV through prophylactic antiretroviral treatment, to provide counseling, and to link HIV-infected persons to care. However, the uptake of couple testing remains low. This study explores men's views on, and experiences of couple HIV testing during ANC. The study was conducted at two time points, in 2008 and 2009, in the rural Iganga and Mayuge districts of eastern Uganda. We carried out nine focus group discussions, about 10 participants in each, and in-depth interviews with 13 men, all of whom were fathers. Data were collected in the local language, Lusoga, audio-recorded and thereafter translated and transcribed into English and analyzed using content analysis. Men were fully aware of the availability of couple HIV testing, but cited several barriers to their use of these services. The men perceived their marriages as unstable and distrustful, making the idea of couple testing unappealing because of the conflicts it could give rise to. Further, they did not understand why they should be tested if they did not have symptoms. Finally, the perceived stigmatizing nature of HIV care and rude attitudes among health workers at the health facilities led them to view the health facilities providing ANC as unwelcoming. The men in our study had several suggestions for how to improve the current policy: peer sensitization of men, make health facilities less stigmatizing and more male-friendly, train health workers to meet men's needs, and hold discussions between health workers and community members. In summary, pursuing couple HIV testing as a main avenue for making men more willing to test and support PMTCT for their wives, does not seem to work in its current form in this region. HIV services must be better adapted to local gender systems taking into account that incentives, health-seeking behavior and health system barriers differ between men and women.


Epileptic encephalopathy with microcephaly in a patient with asparagine synthetase deficiency: a video-EEG report.
Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the asparagine synthetase gene. It is characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. A decrease in asparagine in CSF or plasma guides subsequent investigations in some cases, but normal values are described in other cases. Therefore, reaching a diagnosis is challenging and relies on exome sequencing. We report the case of a child with progressive microcephaly, irritability, startle reflexes, and jitteriness since birth. Focal clonic and myoclonic seizures, status epilepticus, and infantile spasms appeared in the first months of life. At first, the EEG showed multifocal epileptic activity which later turned into modified hypsarrhythmia and discontinuous activity. Brain MRI showed brain atrophy, a simplified gyral pattern, and poor myelination. Plasma asparagine levels were normal. Due to remote parental consanguinity, a study of contiguous regions of runs of homozygosity was performed, showing a 5-Mb region (chr7:95629078-100679007) including the asparagine synthetase gene. The molecular analysis of this gene led to identification of a novel homozygous missense mutation, c.761G>T(p.Gly254Val), in our patient. The peculiar electroclinical phenotype may lead to diagnostic suspicion and molecular analysis which may benefit genetic counselling. [Published with video sequence].


BERT-5mC: an interpretable model for predicting 5-methylcytosine sites of DNA based on BERT.
DNA 5-methylcytosine (5mC) is widely present in multicellular eukaryotes, which plays important roles in various developmental and physiological processes and a wide range of human diseases. Thus, it is essential to accurately detect the 5mC sites. Although current sequencing technologies can map genome-wide 5mC sites, these experimental methods are both costly and time-consuming. To achieve a fast and accurate prediction of 5mC sites, we propose a new computational approach, BERT-5mC. First, we pre-trained a domain-specific BERT (bidirectional encoder representations from transformers) model by using human promoter sequences as language corpus. BERT is a deep two-way language representation model based on Transformer. Second, we fine-tuned the domain-specific BERT model based on the 5mC training dataset to build the model. The cross-validation results show that our model achieves an AUROC of 0.966 which is higher than other state-of-the-art methods such as iPromoter-5mC, 5mC_Pred, and BiLSTM-5mC. Furthermore, our model was evaluated on the independent test set, which shows that our model achieves an AUROC of 0.966 that is also higher than other state-of-the-art methods. Moreover, we analyzed the attention weights generated by BERT to identify a number of nucleotide distributions that are closely associated with 5mC modifications. To facilitate the use of our model, we built a webserver which can be freely accessed at: http://5mc-pred.zhulab.org.cn.


Therapeutic potential of laminin-biodritin microcapsules for type 1 diabetes mellitus.
Pancreatic islet microencapsulation constitutes an attractive therapy for type 1 diabetes mellitus; however, long-term β-cell function remains a major problem. Loss of extracellular matrix interactions during islet isolation dramatically affects β-cell viability. We have previously shown beneficial effects of laminin (LN) in human islet cultures. Herein, we investigated whether LN could improve the outcome of transplantation after islet microencapsulation in Biodritin, an alginate-based material. To test LN-Biodritin stability, microcapsules were subjected to different types of in vitro stress. Focusing on biocompatibility, empty microcapsules were coincubated with the RAW 264.7 macrophage cell line for up to 24 h, and empty beads were implanted IP in mice and retrieved for analyses after 7 and 30 days. Upon culturing for 48 h, mRNA, protein levels, and caspase 3 activity were evaluated in islets microencapsulated with LN-Biodritin. Mice rendered diabetic by streptozotocin injection were transplanted with microencapsulated islets, followed by assessment of body weight, glycemia, and graft function (evaluated by OGTT). Graft efficiency was observed upon microencapsulated islet explantation. The results obtained showed that LN-Biodritin microcapsules were as stable and biocompatible as Biodritin. Modulation of mRNA and protein levels suggested protection against apoptosis and islet stress. Mice transplanted with LN-Biodritin microencapsulated islets presented a better outcome at 198 days postsurgery. Graft explantation led animals to hyperglycemia. In conclusion, LN-Biodritin constitutes a very promising biomaterial for islet transplantation.


Inpatient Rehabilitation Quality of Care From the Patient's Perspective: Effect of Data Collection Timing and Patient Characteristics.
To compare, by collection time and patient characteristics, inpatient rehabilitation quality measure scores calculated using patient-reported data. Cohort study of rehabilitation inpatients with neurologic conditions who reported their experience of care and pain status at discharge and 1month after discharge. Two inpatient rehabilitation facilities (IRFs). Patients with neurologic conditions (N=391). Not applicable. We calculated 18 quality measure scores using participants' responses to 55 experience of care and health status questions addressing communication, support and encouragement, care coordination, discharge information, goals, new medications, responsiveness of staff, cleanliness, quietness, pain management, care transitions, overall hospital rating, willingness to recommend, and pain. Of the 391 participants reporting at discharge, 277 (71%) also reported postdischarge after multiple attempts by e-mail, mail, and telephone. Discharge experience of care quality scores ranged from 25% (responsiveness of hospital staff) to 75% (willingness to recommend hospital); corresponding postdischarge scores were 32% to 87%, respectively. Five of the 16 experience of care quality scores increased significantly between discharge and postdischarge. The percentage of participants reporting high pain levels at discharge did not change across time periods. Patients with less education, older age, higher motor and cognitive function, and those who were not Hispanic or black had more favorable quality measure scores. Patients' experience of care responses tended to be more favorable after discharge compared to discharge, suggesting that survey timing is important. Responses were more favorable for patients with selected characteristics, suggesting the possible need for risk adjustment if patient-reported quality measure scores are compared across IRFs.


Outcomes from mesenteric-portal axis resection during pancreatectomy.
Due to their complexity and risks, mesenteric-portal axis resection and reconstruction during the pancreatectomy procedure were not recommended back in the early nineties. However, as per technical improvements and the reduction in morbidity and mortality rates, they have been routinely indicated in large medical centers. To show results from cases of patients subjected to mesenteric-portal axis resection during pancreatectomy. Patients subjected to mesenteric-portal axis resection during pancreatectomy were prospectively and consecutively assessed. The procedure was indicated according to anatomical criteria defined by imaging exams or intraoperative assessment. Ten patients, half of them were male, with mean age of 55.7 years (40-76) were included. The most frequent underlying diseases were pancreatic adenocarcinoma and Frantz tumor. The circumferential resection of the portal vein associated with the superior mesenteric vein with splenic vein ligature (4 cases=40%) and the primary anastomosis of the vascular stumps (5 cases=50%) were, respectively, the most performed types of vascular resection and reconstruction. Surgery time ranged from 480 to 600 minutes (average=556 minutes) and postoperative hospitalization time ranged from 9 to 114 days (average=34.8 days). Morbidity rate was 60%, and clinical pancreatic fistula (grade B and C) was the most common complication (3 cases=30%). Mortality rate was 10% (1 case). Mesenteric-portal axis resection is a valid technical procedure. It should be taken into account after a clinical assessment that included not only the patients' clinical condition but also the technical and anatomical conditions of the mesenteric-portal axis tumor infiltration as well as life expectancy based on the patient's cancer prognosis.


Outcome of adult cardiac surgery following COVID-19 infection in unvaccinated population in a national tertiary centre.
Ever since COVID-19 was declared a pandemic, the world medical landscape has changed dramatically. As cardiac surgeons we not only have the duty to protect our patients and staff from COVID-19 infection, but we are also tasked with the responsibility to ensure those cardiovascular patients awaiting surgery are not harmed from an extended delay in surgery as the world comes to a halt from COVID-19. Currently there is limited literature on the outcome of cardiac surgery in the pre-operative Covid positive group. In this study we aim to assess the safety and outcome of patients undergoing cardiac surgery following Covid-19 infection. This was a single centre retrospective observational study. All patients undergoing open heart surgery at Institut Jantung Negara from June 2020 to July 2021 were included in this study. Patients who were Covid positive pre-operatively were identified. Data from patient medical records collected contemporaneously were reviewed and analysed, supplemented by telephone call interviews after discharge. 2368 patients underwent open heart surgery from June 2020 until July 2021 in our centre. Of these, 0.5% (12 patients) were identified as Covid positive pre-operatively. Mean age of patients were 59.1 ± 14.8 years old. Mean Ejection Fraction was 46.4 ± 12.9. Most patients (75%) were asymptomatic with covid infection and only one patient were admitted to hospital for Covid infection. Mean duration from Covid PCR positive swab to surgery were 46.3 ± 32.7days. Most of the patients (66.7%) underwent operation on an emergency or urgent basis. Median time to extubation was 1 day. Median ICU length of stay was 1 day. 25% patients required non-invasive ventilation post-operatively and one patient was discharged home on long term oxygen therapy. There were 2 deaths- none of which were covid related mortality. Cardiac surgery could be performed safely in patients with pre-operative Covid-19 infection after a period of recovery, especially in the asymptomatic to mild category of infection. Multi-disciplinary team approach may be useful in deciding the timing of surgery for complex cases.


Solitary spinal artery aneurysms as a rare source of spinal subarachnoid hemorrhage: potential etiology and treatment strategy.
Solitary aneurysms of spinal arteries lacking associated vascular malformations are rare. We report three patients with spinal subarachnoid hemorrhage (SAH) due to rupture of such aneurysms, which regressed spontaneously, as confirmed on conventional angiography. One patient had spinal SAH with presumed spontaneous dissection of a segmental artery. In the other two, SAH resulted from ruptured fusiform aneurysms of the artery of Adamkiewicz immediately proximal to the anterior spinal artery. Solitary aneurysms of the spinal arteries appear to be etiopathologic entities completely different from intracranial aneurysms. Spontaneous occlusion seems to be common, justifying a wait-and-see strategy rather than urgent treatment.


Macrophage inflammatory factors promote epithelial-mesenchymal transition in breast cancer.
The majority of breast cancers (90-95%) arise due to mediators distinct from inherited genetic mutations. One major mediator of breast cancer involves chronic inflammation. M1 macrophages are an integral component of chronic inflammation and the breast cancer tumor microenvironment (TME). Previous studies have demonstrated that up to 50% of the breast tumor comprise of tumor-associated macrophages (TAMs) and increased TAM infiltration has been associated with poor patient prognosis. Furthermore, breast cancer associated deaths are predominantly attributed to invasive cancers and metastasis with epithelial-mesenchymal transition (EMT) being implicated. In this study, we investigated the effects of cellular crosstalk between TAMs and breast cancer using an in vitro model system. M1 polarized THP-1 macrophage conditioned media (CM) was generated and used to evaluate cellular and functional changes of breast cancer lines T47D and MCF-7. We observed that T47D and MCF-7 exhibited a partial EMT phenotype in the presence of activated THP-1 CM. Additionally, MCF-7 displayed a significant increase in migratory and invasive properties. We conclude that M1 secretory factors can promote a partial EMT of epithelial-like breast cancer cells. The targeting of M1 macrophages or their secretory components may inhibit EMT and limit the invasive potential of breast cancer.


Facial nerve palsy in otitis externa: A red flag?
Otitis externa is an infection of the external auditory canal. It rarely results in facial palsy except in severe cases such as necrotizing otitis externa, which is a life-threatening invasive infection of the external auditory canal. Early recognition with prompt and appropriate treatment of necrotizing otitis externa is crucial to prevent more sinister complications. Here we report a case of an elderly gentleman who presented with otitis externa and developed facial palsy a month later. We identified possible problems that may have led to the complication so that such an occurrence can be prevented in the future.


Pregnancy, parenthood, and fertility in the orthopaedic surgeon.
As an increasing number of female surgeons are choosing orthopaedics, it is important to recognize the impact of pregnancy within this cohort. The aim of this review was to examine common themes and data surrounding pregnancy, parenthood, and fertility within orthopaedics. A systematic review was conducted by searching Medline, Emcare, Embase, PsycINFO, OrthoSearch, and the Cochrane Library in November 2022. The Preferred Reporting Items for Systematic Reviews and Meta Analysis were adhered to. Original research papers that focused on pregnancy and/or parenthood within orthopaedic surgery were included for review. Of 1,205 papers, 19 met the inclusion criteria. Our results found that orthopaedic surgeons have higher reported rates of obstetric complications, congenital abnormalities, and infertility compared to the general population. They were noted to have children at a later age and voluntarily delayed childbearing. Negative perceptions of pregnancy from fellow trainees and programme directors were identified. Female orthopaedic surgeons have high rates of obstetric complications and infertility. Negative perceptions surrounding pregnancy can lead to orthopaedic surgeons voluntarily delaying childbearing. There is a need for a pregnancy-positive culture shift combined with formalized guidelines and female mentorship to create a more supportive environment for pregnancy within orthopaedic surgery.


Oxygen free radicals: effects in the newborn period.
Free radical production occurs continuously in all cells as a by-product of cell metabolism. In tandem, the human body has developed endogenous antioxidant systems as well as taken advantage of dietary exogenous antioxidants to process and detoxify free radicals appropriately. However, certain conditions may increase free radical production beyond the body's endogenous and exogenous antioxidant systems. The neonatal period is a vulnerable time for free radical damage and injury, particularly for preterm infants whose antioxidant defense systems have not fully matured. Endogenous and passively acquired exogenous antioxidant defense systems do not accelerate in maturation until late in the third trimester. To explore the complexities of these concepts, this article includes a description, an evolutionary perspective of oxygen, and a basic background on free radical chemistry in biology. In addition, this chemistry is applied to the etiology of many of the most common diseases seen in the neonatal period. Finally, the current research addressing clinical strategies in this area is critically appraised. Implications for practice and directions for further research are presented with an emphasis on strategies that support the prudent use of oxygen therapies.


Cell shape dynamics in Escherichia coli.
Bacteria are the simplest living organisms. In particular, Escherichia coli has been extensively studied and it has become one of the standard model systems in microbiology. However, optical microscopy studies of single E. coli have been limited by its small size, approximately 1 x 3 microm, not much larger than the optical resolution, approximately 0.25 microm. As a result, not enough quantitative dynamical information on the life cycle of single E. coli is presently available. We suggest that, by careful analysis of images from phase contrast and fluorescence time-lapse microscopy, this limitation can be bypassed. For example, we show that applying this approach to monitoring morphogenesis in individual E. coli leads to a simple, quantitative description of this process. First, we find the time when the formation of the septum starts, tau(c). It occurs much earlier than the time when the constriction can be directly observed by phase contrast. Second, we find that the growth law of single cells is more likely bilinear/trilinear than exponential. This is further supported by the relations that hold between the corresponding growth rates. These methods could be further extended to study the dynamics of cell components, e.g., the nucleoid and the Z-ring.


[Hemolytic activity of Vibrio cholerae eltor and V. cholerae O139 toxigenic and nontoxigenic strains].
A total of 20 ctx- and 16 ctx+ V. cholerae eltor strains, 20 ctx- and 22 ctx+ V. cholerae O139 strains were under study. Hemolytic activity was tested in modified Greig test with sheep, guinea pig and rabbit red blood cells. The comparative study of the hemolytic properties of V. cholerae O1 and O139 under different conditions of cultivation demonstrated their capacity of lysing sheep red blood cells (SRBC) irrespective of the presence of toxigenic properties. A wider spectrum of lytic activity of ctx- strains in Greig test with respect to red blood cells of different animals and the capacity of lysing SRBC, most resistant to the action of toxin, may be due to a considerably greater content of Hly+ clones in their population.


Human blood monocytes: stimulators of granulocyte and mononuclear colony formation in vitro.
Human blood monocytes in a feeder layer or by use for conditioning medium produced a colony-stimulating factor capable of stimulating the in vitro growth of colonies of granulocytes and mononuclear cells from human and murine marrow. Lymphocytes and neutrophils did not stimulate colony formation, and medium conditioned by neutrophils was inhibitory. This suggests that the monocyte may control granulocyte proliferation and maturation.


Skin toxins in coral-associated Gobiodon species (Teleostei: Gobiidae) affect predator preference and prey survival.
Predation risk is high for the many small coral reef fishes, requiring successful sheltering or other predator defence mechanisms. Coral-dwelling gobies of the genus Gobiodon live in close association with scleractinian corals of the genus Acropora. Earlier studies indicated that the low movement frequency of adult fishes and the development of skin toxins (crinotoxicity) are predation avoidance mechanisms. Although past experiments showed that predators refuse food prepared with goby skin mucus, direct predator-prey interactions have not been studied. The present study compares the toxicity levels of two crinotoxic coral gobies - Gobiodon histrio, representative of a conspicuously coloured species, and Gobiodon sp.3 with cryptic coloration - using a standard bioassay method. The results show that toxin levels of both species differ significantly shortly after mucus release but become similar over time. Predator preferences were tested experimentally in an aquarium in which the two gobies and a juvenile damselfish Chromis viridis were exposed to the small grouper Epinephelus fasciatus. Video-analysis revealed that although coral gobies are potential prey, E. fasciatus clearly preferred the non-toxic control fish (C. viridis) over Gobiodon. When targeting a goby, the predator did not prefer one species over the other. Contrary to our expectations that toxic gobies are generally avoided, gobies were often captured, but they were expelled quickly, repeatedly and alive. This unusual post-capture avoidance confirms that these gobies have a very good chance of surviving attacks in the field due to their skin toxins. Nonetheless, some gobies were consumed: the coral shelter may therefore also provide additional protection, with toxins protecting them mainly during movement between corals. In summary, chemical deterrence by crinotoxic fishes seems to be far more efficient in predation avoidance than in physical deterrence involving body squamation and/or strong fin spines.


Multifactorial Design of a Supramolecular Peptide Anti-IL-17 Vaccine Toward the Treatment of Psoriasis.
Current treatments for chronic immune-mediated diseases such as psoriasis, rheumatoid arthritis, or Crohn's disease commonly rely on cytokine neutralization using monoclonal antibodies; however, such approaches have drawbacks. Frequent repeated dosing can lead to the formation of anti-drug antibodies and patient compliance issues, and it is difficult to identify a single antibody that is broadly efficacious across diverse patient populations. As an alternative to monoclonal antibody therapy, anti-cytokine immunization is a potential means for long-term therapeutic control of chronic inflammatory diseases. Here we report a supramolecular peptide-based approach for raising antibodies against IL-17 and demonstrate its efficacy in a murine model of psoriasis. B-cell epitopes from IL-17 were co-assembled with the universal T-cell epitope PADRE using the Q11 self-assembling peptide nanofiber system. These materials, with or without adjuvants, raised antibody responses against IL-17. Exploiting the modularity of the system, multifactorial experimental designs were used to select formulations maximizing titer and avidity. In a mouse model of psoriasis induced by imiquimod, unadjuvanted nanofibers had therapeutic efficacy, which could be enhanced with alum adjuvant but reversed with CpG adjuvant. Measurements of antibody subclass induced by adjuvanted and unadjuvanted formulations revealed strong correlations between therapeutic efficacy and titers of IgG1 (improved efficacy) or IgG2b (worsened efficacy). These findings have important implications for the development of anti-cytokine active immunotherapies and suggest that immune phenotype is an important metric for eliciting therapeutic anti-cytokine antibody responses.


Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate.
Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.


Cardiotoxicity of high-dose-rate epirubicin evaluated by angiocardioscintigraphy.
Cardiotoxicity of high dose rate epirubicin (140-160 mg/m(2) as a bolus every 21 days up to a cumulative dose of 1280 mg/m(2)) was evaluated by angiocardioscintigraphy in 121 patients with advanced neoplastic disease and no preexisting cardiac risk factors. LVEF was measured in each patient before chemotherapy and during the treatment at different epirubicin cumulative dosages. The cases were subdivided into 3 groups: Group A=121 basal studies; Group B=93 studies performed under 800 mg/m(2); Group C=44 studies performed over 800 mg/m(2). A statistically significant decrease of LVEF was observed only at cumulative doses over 800 mg/m(2) (mean LVEF: 53% +/- 11% in Group C vs 64% +/- 7% in Group A). In no case was chemotherapy stopped prematurely and no case of heart failure was observed. A decrease of LVEF 10 units was recorded in 15 patients and 12 of them had been treated with over 800 mg/m(2). No clinical signs of severe cardiac failure were observed in these patients during a follow-up of 5-17 months. In conclusion, epirubicin treatment at high dose rate up to a cumulative dose of 1000 mg/m(2) does not increase the risk of clinically relevant cardiomyopathy and an LVEF decrease of 10 units should not in itself lead to chemotherapy termination in responsive patients.


Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC.
The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.


Inhibition of mechanical activity by neurotensin in rat proximal colon: involvement of nitric oxide.
The aim of the present study was to define the nature of inhibitory action of neurotensin in rat proximal colon. Mechanical activity was detected as changes of intraluminal pressure. Neurotensin (10(-10) to 10(-7) M), in the presence of atropine (10(-6) M), guanethidine (10(-6) M), and nifedipine (10(-8) M), induced a tetrodotoxin-insensitive inhibitory effect characterized by the complete disappearance of the spontaneous phasic contractions. The inhibitory effect of neurotensin (10(-7) M) was abolished by scorpion venom (Leiurus quinquestriatus hebraeus) (10(-6) g/ml) or high K+ (40 mM KCl), whereas it persisted in the presence of omega-conotoxin GVIA, (10(-7) M). N omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M to 3 x 10(-4) M) antagonized the inhibitory response to neurotensin but did not affect the response to norepinephrine. L-Arginine (5 x 10(-3) M) prevented the effect of L-NAME. The contractile action of neurotensin, observed in the absence of atropine and nifedipine, was potentiated by L-NAME (10(-4) M); L-arginine (5 x 10(-3) M) prevented the L-NAME effect. The present results suggest that in rat proximal colon the inhibitory action of neurotensin is largely due to production of nitric oxide (NO), likely released from neural prejunctional sites. Ca2+ influx through N-type channels is not a required step in the mechanism of neurotensin inhibitory action.


Current Status of β-Thalassemic Burden in India.
Thalassemia is a major public health concern in India. The thalassemic burden in India is high, with an estimated 100,000 patients diagnosed with β-thalassemia syndrome. However, the exact number is unknown because of the absence of National Registries for patients. India alone contributes to approximately 25% of the global β-thalassemia burden. A possible option to control this burden is to endorse education and awareness programs, compulsory prenatal screening, and develop suitable facilities for genetic counseling, and availability of cost-effective diagnostic tests in India, especially in rural areas. In addition to the various clinical complications associated with thalassemia, lifelong intervention creates mental and physical trauma in patients and their relatives. Government and nongovernment organizations have initiated screening programs to prevent thalassemia. However, prenatal screening is not mandatory, and the reachability of screening programs in rural areas is yet to begin. This review article will discuss the progress in thalassemia research in India, including its prevalence, spectrum of β-thalassemia mutations, preventive and therapeutic measures, and awareness programs. More importantly, we will discuss the need and roadmap to strengthen prevention programs in India.


Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro.
The interaction of hepatocyte growth factor (HGF) with c-Met has been implicated in morphogenesis of the kidney, lung, mammary gland, liver, placenta, and limb bud. HGF is secreted as an inactive zymogen and must be cleaved by a serine protease to initiate Met signaling. We show here that a serine protease specific for HGF, HGF activator (HGFA), is expressed and activated by the ureteric bud of the developing kidney in vivo and in vitro. Inhibition of HGFA activity with serine protease inhibitors reduced ureteric bud branching and inhibited glomerulogenesis and nephrogenesis. Activated HGF rescued developing kidneys from the effects of inhibitors. HGFA was localized around the tips of the ureteric bud in developing kidneys, while HGF was expressed diffusely throughout the mesenchyme. These data show that expression of HGF is not sufficient for development, but that its activation is also required. The localization of HGFA to the ureteric bud and the mesenchyme immediately adjacent to it suggests that HGFA creates a gradient of HGF activity in the developing kidney. The creation and shape of gradients of activated HGF by the localized secretion of HGF activators could play an important role in pattern formation by HGF responsive tissues.


Toll-like receptor 4 orchestrates neutrophil recruitment into airways during the first hours of Bordetella pertussis infection.
Most of the knowledge on the impact of Bordetella pertussis lipo-oligosaccharide (LOS) on the infectious process was obtained when the bacteria was established within the host. The aim of the present work was to determine the role of TLR4 at a very early step of the infectious process. To this end we used a transcriptomic approach on B. pertussis intranasal infection model in C3H/HeN, a TLR4-competent mouse strain, and C3H/HeJ, a TLR4-deficient mouse strain. The expression of approximately 140 genes was significantly changed 2 h post-infection in the C3H/HeN animals compared to the C3H/HeJ animals, which were essentially non-responders at this early time point. Pathways specific for immunity and defense, chemokine- and cytokine-mediated functions and TLR signaling, were activated upon infection in the TLR4 competent mice either at 2 h or 24 h. Furthermore, we observed that TLR4 signaling is absolutely required to promote the rapid recruitment of neutrophils into the airways. Interestingly, the depletion of those neutrophils impacted on B. pertussis lung counts in the first three days, thereby exacerbating the lung infection. In summary, we determined that TLR4 is a central player in initial neutrophil recruitment and orchestration of the very early innate defense against B. pertussis.


Influence of body size on oxygen consumption during bicycling.
Energy in bicycling is primarily expended to overcome air resistance, which is proportional to a cyclist's surface area (SA). Thus we hypothesized that large cyclists should have a lower O2 consumption normalized to body weight (VO2/BW) than small cyclists because of the former's lower SA/BW. We measured the VO2/BW of small (BW = 59.4 +/- 4.1 kg) and large (BW = 84.4 +/- 3.2 kg) cyclists while they bicycled on a flat road at 10, 15, and 20 mph. The large cyclists had a 22% lower VO2/BW than the small cyclists at all speeds. However, the SA/BW ratio of the large cyclists was only 11% lower than that of the small cyclists. We then photographically determined the frontal area (FA) of the cyclists in a racing posture, and found that the large cyclists had a 16% lower FA/BW ratio than the small cyclists. We conclude that large cyclists are at a distinct advantage, in terms of VO2/BW, while bicycling on level roads, and this advantage is principally due to their lower FA/BW ratio.


Tet DNA demethylase is required for plasma cell differentiation by controlling expression levels of IRF4.
Antibodies produced by plasma cells are critical for protection from infection. It has been demonstrated that global epigenetic modification, such as changes in DNA methylation, occurs during differentiation of plasma cells from B cells. However, the precise mechanisms by which DNA methylation controls plasma cell differentiation are not fully understood. We examined the effect of deficiency of DNA demethylases, Tet2 and Tet3, on B-cell activation and plasma cell differentiation, by generating conditional Tet2/3 double-KO (Tet dKO) B cells. We found that Tet dKO B cells failed to differentiate into plasma cells upon immunization with antigens. Tet dKO B cells proliferated normally and were capable of generating cells with IRF4int, but not with IRF4hi, the majority of which were CD138+ plasma cells. IRF4 overexpression rescued the defect of Tet dKO B cells in plasma cell differentiation, suggesting that Tet2/3-dependent high IRF4 expression is required for plasma cell differentiation. We identified CpG sites in the Irf4 locus that were demethylated specifically in plasma cells and in a Tet2/3-dependent manner. Our results suggest that Tet2/3-dependent demethylation of these CpG sites is dispensable for initial IRF4 expression but is essential for high IRF4 expression which is prerequisite for plasma cell differentiation.


Demographic Characteristics, Health Behaviors Before and During Pregnancy, and Pregnancy and Birth Outcomes in Mothers with Different Pregnancy Planning Status.
Studies on pregnancy intentions and their consequences have yielded mixed results. Here, we comprehensively analyzed the maternal characteristics, health behaviors before and during pregnancy, as well as pregnancy and birth outcomes, across three different pregnancy planning status in 861 women participating in an ongoing Asian mother-offspring cohort study. At 26-28 weeks' gestation, the women's intention and enthusiasm toward their pregnancy were used to classify their pregnancy into planned or unplanned, and unplanned pregnancy was further subdivided into mistimed or unintended. Data on maternal characteristics, health behaviors, and pregnancy outcomes up to that stage were recorded. After delivery, birth outcomes of the offspring were recorded. Linear and logistic regression analyses were performed. Overall, 56 % had a planned pregnancy, 39 % mistimed, and 5 % unintended. Compared to women who planned their pregnancy, women with mistimed pregnancy had higher body mass index and were more likely to have cigarette smoke exposure and less likely to have folic acid supplementation. At 26-28 weeks' gestation, unintended pregnancy was associated with increased anxiety. Neonates of mistimed pregnancy had shorter birth length compared to those of planned pregnancy, even after adjustment for maternal baseline demographics. These findings suggest that mothers who did not plan their pregnancy had less desirable characteristics or health behaviors before and during pregnancy and poorer pregnancy and birth outcomes. Shorter birth length in mistimed pregnancy may be attributed to maternal behaviors before or in the early stages of pregnancy, therefore highlighting the importance of preconception health promotion and screening for women of child-bearing age.


Evaluation of selected risk factors of cardiovascular diseases among patients after kidney transplantation, with particular focus on the role of 24-hour automatic blood pressure measurement in the diagnosis of hypertension: an introductory report.
Arterial hypertension is a donor-related and modifiable risk factor in a graft dysfunction. The aim of the study was to perform a multi-factor analysis describing the relations between arterial hypertension and clinical parameters of a graft recipient. Fifty patients 3 months after a kidney transplant took part in the study. The following research tools were used: (1) 24-hour Ambulatory Blood Pressure Monitoring, ABPM; (2) traditional method - office BP; (3) the authors' questionnaire form, (4) Morisky-Green test for self-evaluation of the compliance level; (5) disease history. The relevance level was p<0.05. ABPM results showed that only 8 (16%) renal transplant recipients are normotensive without any antihypertensive drugs. It was shown through ABPM that insufficient controlling of hypertension was observed in 22 patients (44%). It was shown that 9 patients (18%) had masked hypertension and 5 patients (10%) white-coat hypertension. Eight patients (16%) showed controlled daily rhythm of blood pressure ("dippers"). No statistically significant correlation between ABPM and office BP and creatinine level was observed. The results of the study show insufficient control of arterial hypertension and the occurrence of masked hypertension and the white-coat effect in patients after KTx. ABPM should be routinely performed in post-KTx patients. Nonadherence to regular taking of medication and improper lifestyle of patients in the third month after KTx are not a risk factor in higher values of arterial hypertension and higher level of creatinine.


Glycoproteins of the AKR leukaemia cell surface and their relevance to leukaemia-specific surface antigens.
An attempt has been made to prepare antibodies against leukaemia-specific surface antigens by immunizing (C57 B1/6 X C3H/He)F1 mice with formaldehyde-stabilized AKR leukaemic cells. The presence of antibodies was examined by indirect immunofluorescence microscopy (IFM) and the indirect antiglobulin rosetting reaction (IARR). Galactose oxidase treatment destroyed the ability of leukaemic cells to react with antibodies prepared in the hybrid mice, an effect that was reversed by treating the enzyme-modified cells with borohydride. Analysis by immunoprecipitation and polyacrylamide gel electrophoresis of leukaemic cells, labelled by the galactose oxidase/[3H]-NaBH4 technique, indicated that a group of glycoproteins of apparent molecular weight greater than 70 000 was involved. Antibodies could be raised in AKR mice to the same group of glycoproteins by immunization with irradiated leukaemic cells or irradiated neuraminidase-treated leukaemic cells. The level of antibody raised in AKR mice had no effect on the growth of leukaemic lymphoblasts introduced subcutaneously into the host. Antibodies prepared in hybrid mice against leukaemic cells also were absorbed by lymphoid cells of pre-leukaemic 6-month-old AKR mice, indicating that contrary to previous claims in the literature antigens detected by such antisera are not related to malignancy. Hybrid mouse serum cross-reacted with antigens from purified RNA virus isolated from Abelson lymphoma, as demonstrated by the immunoelectrophoretic blotting technique. The pattern of reactivity was not appreciably altered following the absorption of antibodies directed against leukaemic cells. It is concluded that the glycoproteins detected by us may not be viral antigens but normal high molecular weight lymphoid glycoproteins with altered glycosylation patterns that are induced when the viral genomes are expressed.


Conventionally fractionated radiation therapy versus stereotactic body radiation therapy for locally advanced pancreatic cancer (CRiSP): An international systematic review and meta-analysis.
The goal of this study was to characterize the efficacy and safety of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy with concurrent chemotherapy (CFRT) for the definitive treatment of locally advanced pancreatic cancer. The primary outcome measure was efficacy, defined by 2-year overall survival (OS). Secondary outcomes were incidence of any grade 3/4 toxicity and 1-year OS. A PICOS/PRISMA/MOOSE selection protocol was used to identify eligible studies. Inclusion criteria were: 1) patients diagnosed with locally advanced N0-1 M0 pancreatic cancer; 2) CFRT 1.8 to 2.0 Gy/fraction with chemotherapy per protocol or SBRT ≥5 Gy/fraction in ≤5 fractions; 3) either no control group or another definitive chemotherapy or radiation therapy arm; 4) at least 1 of the outcome measures reported; and 5) single or multi-arm phase 2/3 prospective study for CFRT and/or phase 1/2 or retrospective study for SBRT. Neoadjuvant and/or adjuvant chemotherapy was prescribed per protocol specifications. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method to characterize summary effect sizes for each outcome. A total of 470 studies were initially screened; of these, 9 studies assessed SBRT and 11 studies assessed CFRT. For SBRT, the median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. For CFRT, doses ranged from 45 to 54 Gy in 1.8- to 2.0-Gy fractions, with the majority of studies delivering 50.4 Gy in 28 fractions with concurrent gemcitabine. The random effects estimate for 2-year OS was 26.9% (95% CI, 20.6%-33.6%) for SBRT versus 13.7% (95% CI, 8.9%-19.3%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for 1-year OS was 53.7% (95% CI, 39.3%-67.9%) for SBRT versus 49.3% (95% CI, 39.3%-59.4%) for CFRT, and was not statistically significant. The random effects estimate for acute grade 3/4 toxicity was 5.6% (95% CI, 0.0%-20.0%) for SBRT versus 37.7% (95% CI, 24.0%-52.5%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for late grade 3/4 toxicity was 9.0% for SBRT (95% CI, 3.3%-17.1%) versus 10.1% (95% CI, 1.8%-23.8%) for CFRT, which was not statistically significant. These results suggest that SBRT for LAPC may result in a modest improvement in 2-year OS with decreased rates of acute grade 3/4 toxicity and no change in 1-year-OS or late toxicity. Further study into the use of stereotactic body radiation therapy for these patients is needed.


A Functionally Different Immune Phenotype in Cattle Is Associated With Higher Mastitis Incidence.
A novel vaccine against bovine viral diarrhea (BVD) induced pathogenic antibody production in 5-10% of BVD-vaccinated cows. Transfer of these antibodies via colostrum caused Bovine neonatal pancytopenia (BNP) in calves, with a lethality rate of 90%. The exact immunological mechanisms behind the onset of BNP are not fully understood to date. To gain further insight into these mechanisms, we analyzed the immune proteome from alloreactive antibody producers (BNP cows) and non-responders. After in vitro stimulation of peripheral blood derived lymphocytes (PBL), we detected distinctly deviant expression levels of several master regulators of immune responses in BNP cells, pointing to a changed immune phenotype with severe dysregulation of immune response in BNP cows. Interestingly, we also found this response pattern in 22% of non-BVD-vaccinated cows, indicating a genetic predisposition of this immune deviant (ID) phenotype in cattle. We additionally analyzed the functional correlation of the ID phenotype with 10 health parameters and 6 diseases in a retrospective study over 38 months. The significantly increased prevalence of mastitis among ID cows emphasizes the clinical relevance of this deviant immune response and its potential impact on the ability to fight infections.


Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis.
The function of some genetic variants associated with brain-relevant traits has been explained through colocalization with expression quantitative trait loci (eQTL) conducted in bulk post-mortem adult brain tissue. However, many brain-trait associated loci have unknown cellular or molecular function. These genetic variants may exert context-specific function on different molecular phenotypes including post-transcriptional changes. Here, we identified genetic regulation of RNA-editing and alternative polyadenylation (APA), within a cell-type-specific population of human neural progenitors and neurons. More RNA-editing and isoforms utilizing longer polyadenylation sequences were observed in neurons, likely due to higher expression of genes encoding the proteins mediating these post-transcriptional events. We also detected hundreds of cell-type-specific editing quantitative trait loci (edQTLs) and alternative polyadenylation QTLs (apaQTLs). We found colocalizations of a neuron edQTL in CCDC88A with educational attainment and a progenitor apaQTL in EP300 with schizophrenia, suggesting genetically mediated post-transcriptional regulation during brain development lead to differences in brain function.


Utility of AAOS OITE scores in predicting ABOS Part I outcomes: AAOS exhibit selection.
Residency programs commonly use performance on the Orthopaedic In-Training Examination (OITE) developed by the American Academy of Orthopaedic Surgeons (AAOS) to identify residents who are lagging behind their peers and at risk for failing Part I of the American Board of Orthopaedic Surgery (ABOS) Certifying Examination. This study was designed to investigate the utility of the OITE score as a predictor of ABOS Part I performance. Results for 3132 examinees who took Part I of the ABOS examination for the first time from 2002 to 2006 were matched with records from the 1997 to 2006 OITE tests; at least one OITE score was located for 2852 (91%) of the ABOS Part I examinees. After OITE performance was rescaled to place scores from different test years on comparable scales, descriptive statistics and correlations between ABOS and OITE scores were computed, and regression analyses were conducted to predict ABOS results from OITE performance. Substantial increases in the mean OITE score were observed as residents progressed through training. Stronger correlations were observed between OITE and ABOS performance during later years in training, reaching a maximum of 0.53 in years 3 and 4. Logistic regression results indicated that residents with an OITE score below the 10th percentile were much more likely to fail Part I compared with those with an OITE score above the 50th percentile. OITE performance was a good predictor of the ABOS score and pass-fail outcome; the OITE can be used effectively for early identification of residents at risk for failing the ABOS Part I examination.


Assessment of Changes in the Oral Microbiome That Occur in Dogs with Periodontal Disease.
The oral microbiome in dogs is a complex community. Under some circumstances, it contributes to periodontal disease, a prevalent inflammatory disease characterized by a complex interaction between oral microbes and the immune system. Porphyromonas and Tannerella spp. are usually dominant in this disease. How the oral microbiome community is altered in periodontal disease, especially sub-dominant microbial populations is unclear. Moreover, how microbiome functions are altered in this disease has not been studied. In this study, we compared the composition and the predicted functions of the microbiome of the cavity of healthy dogs to those with from periodontal disease. The microbiome of both groups clustered separately, indicating important differences. Periodontal disease resulted in a significant increase in Bacteroidetes and reductions in Actinobacteria and Proteobacteria. Porphyromonas abundance increased 2.7 times in periodontal disease, accompanied by increases in Bacteroides and Fusobacterium. It was predicted that aerobic respiratory processes are decreased in periodontal disease. Enrichment in fermentative processes and anaerobic glycolysis were suggestive of an anaerobic environment, also characterized by higher lipopolysaccharide biosynthesis. This study contributes to a better understanding of how periodontal disease modifies the oral microbiome and makes a prediction of the metabolic pathways that contribute to the inflammatory process observed in periodontal disease.


Impact of separating drug prescribing and dispensing on provider behaviour: Taiwan's experience.
In many Asian countries, physicians both prescribe and dispense drugs. This practice is hypothesized to have caused high drug expenditure and widespread prescription of antibiotics in Asia. Recently, Taiwan implemented the separation policy on an experimental basis. This paper's objective is to empirically evaluate the impact of Taiwan's reform to separate drug prescribing and dispensing on drug expenditure and total health expenditure. The research design consists of a pre/post comparison of the experimental with the control sites (difference-in-difference). Separation policy was implemented in Kaohsung and Taipei in March 1997, and expanded to Chia-yi and Taichung in March 1998. Changes in drug prescription behaviour before and after implementation in these two pairs of experimental cities were compared to Hsin-chu and Tainan (control), where separation policy was not implemented during the study period. To reduce resistance, providers in experimental sites were allowed to hire on-site pharmacists and dispense drugs through them if they chose to do so. Our study sample consists of all outpatient visits to clinics in the study sites between December 1996 and June 1998, with a total of 55.23 million claim records. The drug prescription rate, drug expenditure and total health expenditure per visit were the main outcome measures. We found that the probability of prescription and drug expenditure per visit were, respectively, 17-34% and 12-36% less among visits to clinics without on-site pharmacists, compared with the control sites. However, no difference in total health expenditure was found between these two types of visits. Hence, the separation policy could be effective in reducing drug expenditure and affecting prescription behaviour, but is less certain as a policy for reducing total health expenditure. We also found that the policy has practically no effect on clinics that have on-site pharmacists.


Impact of the 2018 Japan Floods on benzodiazepine use: a longitudinal analysis based on the National Database of Health Insurance Claims.
Natural disaster has an impact on mental health. The 2018 Japan Floods, which took place in July 2018 were one of the largest water disasters in Japan's recorded history. We aimed to evaluate the change in the number of benzodiazepine prescriptions by physicians before and after the disaster. A retrospective cohort study based on the National Database of Health Insurance Claims was conducted in the flood-stricken areas between July 2017 and June 2019. The subjects were divided between victims and non-victims according to certification by local governments. Members of both groups were then categorized into three groups based on their pre-flood use of benzodiazepines: non-user, occasional user, and continuous user. Difference-in-differences (DID) analysis with a logistic regression model was conducted to estimate the effect of the disaster among victims by comparing the occurrence of benzodiazepine prescriptions before and after the disaster. Of 5,000,129 people enrolled, 31,235 were victims. Among all participants, the mean prescription rate for benzodiazepines in victims before the disaster (11.3%) increased to 11.8% after the disaster, while that in non-victims (8.3%) decreased to 7.9%. The DID analysis revealed that benzodiazepine prescription among victims significantly increased immediately after the disaster (adjusted ratio of odds ratios (ROR) 1.07: 95% confidence interval 1.05-1.11), and the effect of the disaster persisted even 1 year after the disaster (adjusted ROR 1.2: 95% confidence interval 1.16-1.24). The flood increased the number of benzodiazepines prescriptions among victims, and the effect persisted for at least 1 year.


[Puzzling bipolar disorder].
Despite many advances in making the diagnosis of bipolar disorder, five to twelve years lie between the first affective episode and the introduction of an effective treatment. However, it is estimated that approximately only one-fourth of the patients with bipolar disorder are recognized as such at all. Clinical experience plays an important role in the diagnosis. Manias are often the cause for the first treatment with drugs, but the daily lives of patients with bipolar depression are often clearly more negatively affected. The acute therapy of bipolar depression is more complicated than that of mania and the difficult long-term treatment is always associated with a high suicide risk. A long-term therapy of bipolar disorders is not only meaningful for the prevention of new disease episodes, but also because it has a positive effect on comorbidities.


Cryptococcal meningitis in a newly diagnosed AIDS patient: a case report.
Cryptococcus neoformans is a very important cause of fungal meningitis in immunosuppressed patients To describe a case of cryptococcal meningoencephalitis in an HIV/AIDS patient from the University of Ilorin Teaching Hospital. An 18 -year -old male student presented with cough, weight loss, and fever. He was clinically assessed and had full laboratory investigations including cerebrospinal fluid CSF and then started on chemotherapy. Both the clinical and neurological evaluation of the patient was described along with the laboratory analyses of his CSF. Outcome of how he was managed was also reported. Cryptococcus neoformans presented as an AIDS defining fungal infection for the first time in this 18 year old undergraduate who was infected probably from transfusion of unscreened blood He had advanced HIV infection (CD4+ count of 29 cells/ul) and severe cryptococcal meningoencephalitis. He was unsuccessfully managed with fluconazole, a second choice drug for this condition, amphotericin B being not available. Nigerians should have access to effective blood transfusion services at all public and private hospitals across the country. The National Essential Drug list should be expanded to include drugs such as amphotericin B which hitherto were considered exotic.


Hearing and hair cells.
Animal experiments and human temporal bone studies have indicated that hearing losses may occur in ears that have normal populations of sensory cells. The possibility exists that the hair cells have been rendered non-functional because of ultrastructural damage. Preliminary investigation of cilia on hair cells in areas of suspected damage shows no difference from cilia in similar areas of control ears.


Geographic and ecological distribution of the dengue and chikungunya virus vectors Aedes aegypti and Aedes albopictus in three major Cameroonian towns.
Aedes albopictus (Diptera: Culicidae) was first reported in Central Africa in 2000, together with the indigenous mosquito species Aedes aegypti (Diptera: Culicidae). Because Ae. albopictus can also transmit arboviruses, its introduction is a public health concern. We undertook a comparative study in three Cameroonian towns (Sahelian domain: Garoua; equatorial domain: Douala and Yaoundé) in order to document infestation by the two species and their ecological preferences. High and variable levels of pre-imaginal Ae. aegypti and Ae. albopictus infestation were detected. Only Ae. aegypti was encountered in Garoua, whereas both species were found in Douala and Yaoundé, albeit with significant differences in their relative prevalence. Peridomestic water containers were the most strongly colonized and productive larval habitats for both species. No major differences in types of larval habitat were found, but Ae. albopictus preferentially bred in containers containing plant debris or surrounded by vegetation, whereas Ae. aegypti tended to breed in containers located in environments with a high density of buildings. These findings may have important implications for vector control strategies.


Selective lentiviral-mediated suppression of microRNA124a in the hippocampus evokes antidepressants-like effects in rats.
Several lines of evidences suggest that the brain-derived neutrophic factor (BDNF) is implicated in the pathophysiology of depression. However, the molecular mechanisms are not fully understood. In the current study we aimed to investigate how genetic modulation of BDNF in the hippocampus using microRNa124a (miR124a)-expressing lentiviral vectors (LV) might affect depression-like behavior in adult rats. For this purpose, we assessed the expression level of miR124a and its direct target BDNF in the hippocampus and the cortex after 21-days exposure to social defeat stress. Results demonstrated that miR124a was up-regulated in the hippocampus but not in the cortex. In contrast, and as expected, BDNF transcripts were down-regulated. In a different set of experiments, male Wistar rats received bilateral intra-hippocampal or intra-cortical infusions of BDNF- and miR124a-expressing lentiviral vectors and depression-like behavior was assessed after 21-days social defeat stress using the novelty suppressed feeding, the sucrose preference and the forced swim tests. The results indicated that miR124a overexpression exacerbated depression-like behavior. However, an anti-depressant like effect was observed when BDNF or miR124a-silencers (siR124a) were injected into the hippocampus. Importantly, when expressed into the cortex, LV-miR124a, LV-siR124a and LV-BDNF had no effect on depression. Our findings indicate that hippocampal miR124a and its direct target BDNF play an important role in depression-like behavior. Taken together, the current results reveal, for the first time, a potential molecular regulation of miR124a on BDNF, and the pronounced behavioral consequences of this regulation shed light on the mechanisms underlying BDNF anti-depressant potential.


Developmentally regulated initiation of DNA synthesis by telomerase: evidence for factor-assisted de novo telomere formation.
Telomerase serves a dual role at telomeres, maintaining tracts of telomere repeats and forming telomeres de novo on broken chromosomes in a process called chromosome healing. In ciliates, both mechanisms are readily observed. Vegetatively growing cells maintain pre-existing telomeres, while cells undergoing macronuclear development fragment their chromosomes and form telomeres de novo. Here we provide the first evidence for developmentally regulated initiation of DNA synthesis by telomerase. In vitro assays were conducted with telomerase from vegetative and developing Euplotes macronuclei using chimeric primers that contained non-telomeric 3' ends and an upstream stretch of telomeric DNA. In developing macronuclei, chimeric primers had two fates: nucleotides were either polymerized directly onto the 3' terminus or residues were removed from the 3' end by endonucleolytic cleavage before polymerization began. In contrast, telomerase from vegetative macronuclei used only the cleavage pathway. Telomere repeat addition onto non-telomeric 3' ends was lost when developing macronuclei were lysed and the contents purified on glycerol gradients. However, when fractions from the glycerol gradient were added back to partially purified telomerase, telomere synthesis was restored. The data indicate that a dissociable chromosome healing factor (CHF) collaborates with telomerase to initiate developmentally programmed de novo telomere formation.


Severe Respiratory Failure, Extracorporeal Membrane Oxygenation, and Intracranial Hemorrhage.
For patients supported with veno-venous extracorporeal membrane oxygenation, the occurrence of intracranial hemorrhage is associated with a high mortality. It is unclear whether intracranial hemorrhage is a consequence of the extracorporeal intervention or of the underlying severe respiratory pathology. In a cohort of patients transferred to a regional severe respiratory failure center that routinely employs admission brain imaging, we sought 1) the prevalence of intracranial hemorrhage; 2) survival and neurologic outcomes; and 3) factors associated with intracranial hemorrhage. A single-center, retrospective, observational cohort study. Tertiary referral severe respiratory failure center, university teaching hospital. Patients admitted between December 2011 and February 2016. None. Three hundred forty-two patients were identified: 250 managed with extracorporeal support and 92 managed using conventional ventilation. The prevalence of intracranial hemorrhage was 16.4% in extracorporeal membrane oxygenation patients and 7.6% in conventionally managed patients (p = 0.04). Multivariate analysis revealed factors independently associated with intracranial hemorrhage to be duration of ventilation (d) (odds ratio, 1.13 [95% CI, 1.03-1.23]; p = 0.011) and admission fibrinogen (g/L) (odds ratio, 0.73 [0.57-0.91]; p = 0.009); extracorporeal membrane oxygenation was not an independent risk factor (odds ratio, 3.29 [0.96-15.99]; p = 0.088). In patients who received veno-venous extracorporeal membrane oxygenation, there was no significant difference in 6-month survival between patients with and without intracranial hemorrhage (68.3% vs 76.0%; p = 0.350). Good neurologic function was observed in 92%. We report a higher prevalence of intracranial hemorrhage than has previously been described with high level of neurologically intact survival. Duration of mechanical ventilation and admission fibrinogen, but not exposure to extracorporeal support, are independently associated with intracranial hemorrhage.


Near-infrared luminescent lanthanide MOF barcodes.
We demonstrate the conceptual advantage of using metal-organic frameworks (MOFs) for the creation of a polymetallic material that contains several different near-IR-emitting lanthanide cations and operates as a barcode material with unique luminescence properties. By choosing the ratio of lanthanide salts used during the synthesis, we can control the ratio of lanthanide cations present in the resulting material. We have demonstrated that the emission intensity of each of the different lanthanide cations is proportional to its amount in the MOF crystal, resulting in unique spectroscopic barcodes that depend on the lanthanide cation ratios and compositions.


Alterations in the expression of PDCD4 in ductal carcinoma of the breast.
Programmed cell death 4 gene (PDCD4), an in vivo repressor of transformation, was originally isolated from a human glioma library by screening it with an antibody against a nuclear antigen in proliferating cells. PDCD4 functions as a transformation repressor by inhibiting the activity of the RNA helicase, eIF4A. We previously showed that retinoids, anti-estrogens and HER2/neu antagonist induce PDCD4 expression in human breast cancer cell lines. Very little is known about the expression of PDCD4 in human breast cancer tissues or the significance of the PDCD4 expression in breast cancer. To gain insight into the pattern of the PDCD4 expression in breast tissues, we performed an immunohistochemical analysis of the PDCD4 expression in 80 archived, normal and ductal breast carcinoma tissues (invasive and carcinoma in situ) (DCIS) and correlated PDCD4 expression with expression of known prognostic markers in breast cancer (ER, PR and HER2/neu). To assess the role of methylation on PDCD4 expression in breast cancer cells, breast cancer cell lines were treated with the demethylating agent 5-deoxy-azacytidine and analyzed for PDCD4 expression. We observed primarily nuclear localization of PDCD4 in ductal carcinoma in situ compared to normal breast tissues where the PDCD4 expression was predominantly cytoplasmic. This was seen more frequently in DCIS cases that were ER positive and HER2/neu negative samples. PDCD4 expression was markedly decreased in the invasive ductal carcinoma. We did not observe any significant relationship between PDCD4 expression and the expression of RAR or PR. In T-47D, MDA-MB-435 and MDA-MB-231 cells, treatment with 5-deoxy-azacytidine did not result in an increased expression of PDCD4. The present study demonstrated altered cellular localization of PDCD4 when comparing normal breast to neoplastic breast tissues. In addition, there was a decreased expression of PDCD4 in breast cancer when compared with normal breast tissue. A loss of the PDCD4 expression in breast cancer cell lines does not appear to result from hypermethylation of the PDCD4 promoter.


Highly expressed SLC35F2 in non-small cell lung cancer is associated with pathological staging.
Homo sapiens solute carrier family 35 member F2 (SLC35F2) is highly homologous to the lung squamous cell cancer-related gene, LSCC3, which is highly expressed in lung squamous cell tumour tissues. However, the clinical implication of the SLC35F2 gene in tumour development and progression remains unclear. An affinity-purified polyclonal antibody raised against the human SLC35F2 peptide was used in the immunohistochemical analysis of a non-small cell lung cancer (NSCLC) tissue microarray of human NSCLC (n=129). SLC35F2 protein was also analysed with the same antibody using Western blotting. Total RNAs were extracted from tumour tissues (n=43) and from laser-dissected tumour cells (n=9). SLC35F2 gene expression was detected by fluorescent real-time quantitative PCR and compared to the expression in the corresponding adjacent normal lung tissues. It was found that both the SLC35F2 protein (by IHC analysis) and the SLS35F2 gene transcripts (by Q-PCR analysis) were expressed at significantly higher levels in the NSCLC tumour tissues than in the corresponding adjacent normal lung tissues (p<0.001 and =0.015, respectively). There was a significant correlation between the SLC35F2 transcript and pathological staging (r=0.219, p=0.029), although the correlation between SLC35F2 protein and the staging was not significant (r=0.175). SLC35F2 was highly expressed in NSCLC tissues and the levels of expression, in particular the levels of the SLC35F2 transcript, were associated with NSCLC pathological staging. SLC35F2 appears to have a significant prognostic value in NSCLC.


Retrospective clinical study on outcome in cats with nasal planum squamous cell carcinoma treated with an accelerated radiation protocol.
Cutaneous squamous cell carcinoma of the nasal planum in cats is a common indication for antitumor treatment such as external beam radiation therapy. Curative-intent radiation therapy has been described as a valuable treatment option, resulting in long and stable tumor control in these patients. The aim of the current study was to evaluate outcome and toxicity, as well as possible prognostic factors using an accelerated hypofractionated radiation therapy protocol. Cats with squamous cell carcinoma of the nasal planum treated with an accelerated radiation protocol (10 × 4.8 Gy, over one week) were retrospectively evaluated. Tumor- and treatment-associated variables were evaluated in respect to local control and survival. Forty-four cats met the inclusion criteria for this study. All cats showed complete response to therapy. Median disease-free interval (DFI) for all cases was 916 days (95% CI: 456-1377). One- and two-year DFIs were 71% (95% CI: 56-86%) and 60% (95% CI: 43-77%). Of the tested variables, only tumor volume showed a tendency to influence DFI, with larger tumors having a 5.4 times greater risk of recurrence than the smaller ones (HR 1.33 (95% CI: 0.99-1.79), p = 0.054). Median overall survival (OS) was 902 days (95% CI: 862-942). One- and 2-year OSs were 79.3% (95% CI: 67.3-91.3) and 58.4% (95% CI: 42.8-74). Of the tested variables, again, only tumor volume influenced OS with larger tumors having a 6.3 times greater risk of dying than the smaller ones (HR 1.36 (95% CI: 1.07-1.73), p = 0.010). The acute and late toxicity profile was low and hence clinically acceptable. Curative-intent radiation therapy with an accelerated fractionation schedule can be considered a safe, cosmetically superior treatment option for cutaneous squamous cell carcinomas of the nasal planum in cats, resulting in long and stable tumor control.


Passive Properties of the Wrist and Fingers Following Chronic Hemiparetic Stroke: Interlimb Comparisons in Persons With and Without a Clinical Treatment History That Includes Botulinum Neurotoxin.
Background: Neural impairments that follow hemiparetic stroke may negatively affect passive muscle properties, further limiting recovery. However, factors such as hypertonia, spasticity, and botulinum neurotoxin (BoNT), a common clinical intervention, confound our understanding of muscle properties in chronic stroke. Objective: To determine if muscle passive biomechanical properties are different following prolonged, stroke-induced, altered muscle activation and disuse. Methods: Torques about the metacarpophalangeal and wrist joints were measured in different joint postures in both limbs of participants with hemiparetic stroke. First, we evaluated 27 participants with no history of BoNT; hand impairments ranged from mild to severe. Subsequently, seven participants with a history of BoNT injections were evaluated. To mitigate muscle hypertonia, torques were quantified after an extensive stretching protocol and under conditions that encouraged participants to sleep. EMGs were monitored throughout data collection. Results: Among participants who never received BoNT, no significant differences in passive torques between limbs were observed. Among participants who previously received BoNT injections, passive flexion torques about their paretic wrist and finger joints were larger than their non-paretic limb (average interlimb differences = +42.0 ± 7.6SEM Ncm, +26.9 ± 3.9SEM Ncm, respectively), and the range of motion for passive finger extension was significantly smaller (average interlimb difference = -36.3° ± 4.5°SEM; degrees). Conclusion: Our results suggest that neural impairments that follow chronic, hemiparetic stroke do not lead to passive mechanical changes within the wrist and finger muscles. Rather, consistent with animal studies, the data points to potential adverse effects of BoNT on passive muscle properties post-stroke, which warrant further consideration.


rTMS age-dependent response in treatment-resistant depressed subjects: a mini-review.
In old age, depressive syndromes often affect people with chronic medical illnesses, cognitive impairment, and disability, which can worsen the outcomes of other medical disorders and promote disability. Repetitive magnetic transcranial stimulation (rTMS) is a simple and effective treatment in patients with treatment-resistant depression. Therefore the use of rTMS could be of particular potential benefit in treatment-resistant elderly patients, who often cannot tolerate the higher doses of drugs needed or show phenomena of intolerance and interaction. However, several studies assessing the efficacy of rTMS found smaller response rates in elderly patients when compared to younger samples. Nevertheless, the correlation between age and response is still a controversial issue, and there is no strong evidence to date. The aim of our study was to retest the effectiveness and safety of low-frequency rTMS in a 3 weeks active treatment in a group of resistant-depressed patients, and to investigate the role of age in the response to stimulation treatment. Enrolled in this study were 102 treatment-resistant depressed patients. The patients were treated with low-frequency rTMS over the right dorso-lateral prefrontal cortex (DLPFC) for 3 weeks with a simple protocol (420 pulses per session for 15 sessions). At baseline, at the end of the second week, and at the end of the third week of treatment, the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A) were administered. Low-frequency rTMS on the prefrontal dorsolateral right area resulted in a statistically significant reduction of mean HAM-D scores in the entire group of patients at the end of treatment. The responder's rate in the whole group at the end of the third week was 56.86%. A significant inverse relationship between HAM-D reduction and age was found in the "older" (>60 years old) group, not in the "younger" (<60 years old) group. Results from this study show that low-frequency rTMS over the right DLPFC, with a relatively low number of pulses (420 pulses per session) and a relatively short period of treatment, is effective in the treatment of resistant patients (in a sample also including elderly patients) in a 3-weeks treatment protocol with a low reduction with the progress of age. Furthermore, we found a greater response in younger patients and an inverse correlation between age and treatment response. Adaptations of the protocol according to age are reviewed.


Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies.
To systematically assess credibility and certainty of associations between cannabis, cannabinoids, and cannabis based medicines and human health, from observational studies and randomised controlled trials (RCTs). Umbrella review. PubMed, PsychInfo, Embase, up to 9 February 2022. Systematic reviews with meta-analyses of observational studies and RCTs that have reported on the efficacy and safety of cannabis, cannabinoids, or cannabis based medicines were included. Credibility was graded according to convincing, highly suggestive, suggestive, weak, or not significant (observational evidence), and by GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (RCTs). Quality was assessed with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). Sensitivity analyses were conducted. 101 meta-analyses were included (observational=50, RCTs=51) (AMSTAR 2 high 33, moderate 31, low 32, or critically low 5). From RCTs supported by high to moderate certainty, cannabis based medicines increased adverse events related to the central nervous system (equivalent odds ratio 2.84 (95% confidence interval 2.16 to 3.73)), psychological effects (3.07 (1.79 to 5.26)), and vision (3.00 (1.79 to 5.03)) in people with mixed conditions (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal adverse events, and somnolence among others (GRADE=moderate). Cannabidiol improved 50% reduction of seizures (0.59 (0.38 to 0.92)) and seizure events (0.59 (0.36 to 0.96)) (GRADE=high), but increased pneumonia, gastrointestinal adverse events, and somnolence (GRADE=moderate). For chronic pain, cannabis based medicines or cannabinoids reduced pain by 30% (0.59 (0.37 to 0.93), GRADE=high), across different conditions (n=7), but increased psychological distress. For epilepsy, cannabidiol increased risk of diarrhoea (2.25 (1.33 to 3.81)), had no effect on sleep disruption (GRADE=high), reduced seizures across different populations and measures (n=7), improved global impression (n=2), quality of life, and increased risk of somnolence (GRADE=moderate). In the general population, cannabis worsened positive psychotic symptoms (5.21 (3.36 to 8.01)) and total psychiatric symptoms (7.49 (5.31 to 10.42)) (GRADE=high), negative psychotic symptoms, and cognition (n=11) (GRADE=moderate). In healthy people, cannabinoids improved pain threshold (0.74 (0.59 to 0.91)), unpleasantness (0.60 (0.41 to 0.88)) (GRADE=high). For inflammatory bowel disease, cannabinoids improved quality of life (0.34 (0.22 to 0.53) (GRADE=high). For multiple sclerosis, cannabinoids improved spasticity, pain, but increased risk of dizziness, dry mouth, nausea, somnolence (GRADE=moderate). For cancer, cannabinoids improved sleep disruption, but had gastrointestinal adverse events (n=2) (GRADE=moderate). Cannabis based medicines, cannabis, and cannabinoids resulted in poor tolerability across various conditions (GRADE=moderate). Evidence was convincing from observational studies (main and sensitivity analyses) in pregnant women, small for gestational age (1.61 (1.41 to 1.83)), low birth weight (1.43 (1.27 to 1.62)); in drivers, car crash (1.27 (1.21 to 1.34)); and in the general population, psychosis (1.71 (1.47 to 2.00)). Harmful effects were noted for additional neonatal outcomes, outcomes related to car crash, outcomes in the general population including psychotic symptoms, suicide attempt, depression, and mania, and impaired cognition in healthy cannabis users (all suggestive to highly suggestive). Convincing or converging evidence supports avoidance of cannabis during adolescence and early adulthood, in people prone to or with mental health disorders, in pregnancy and before and while driving. Cannabidiol is effective in people with epilepsy. Cannabis based medicines are effective in people with multiple sclerosis, chronic pain, inflammatory bowel disease, and in palliative medicine but not without adverse events. PROSPERO CRD42018093045. None.


Using a resilience thinking approach to improve coastal governance responses to complexity and uncertainty: a Tasmanian case study, Australia.
Conventional approaches to environmental governance and management are limited in their responses to uncertainty and complexity of social-ecological system (SES) change. Prevailing neoliberal and efficiency-based mindsets tend to focus on avoiding risk and creating "fail-safe" systems. In the last decade, resilience thinking has emerged as a means to transition from risk-averse, and command-and-control governance approaches towards those that are more adaptive, innovative and collaborative. To examine the practical usefulness of a resilience thinking approach, we used a complex, multi-layered case study of Tasmanian coastal governance. Drawing on the diverse expertise and a variety of key governance actors, we identified crucial problems being experienced with the Tasmanian coastal governance regime and discussed potential contributions of resilience thinking to address them. Thematic analysis of the results revealed three major contributions: resilience thinking (1) provides a way to think about change and uncertainty; (2) is compatible with proactive and entrepreneurial leadership; and (3) effectively considers issues of scale in the decision-making process. We conclude by offering practical suggestions towards devolved leadership and improved cross-scale collaboration, and consider the possibility of a hybrid resilience and risk-based approach to coastal management and governance.


Learning contracts in higher professional training: a user's guide.
If the doctor undergoing higher professional training is to make best use of the attachment to a training location, and that training location is to make the most efficient use of the contribution of the trainee, then a written framework such as a learning contract can meet the needs of both. The first stage is to list the learning needs of the individual trainee and to match them with the work experience offered by the training location. Next, the work programme for the coming six to 12 months should be formalised in a learning contract, spelling out the tasks to be performed and the expected training benefit. This is then reviewed at agreed intervals and a written appraisal made. At the end of the attachment the trainee, trainer and any outside accrediting or auditing body, has a written account of what was expected, what was achieved, and the performance of trainee and trainer.


Novel optical scanning cryptography using Fresnel telescope imaging.
We propose a new method called modified optical scanning cryptography using Fresnel telescope imaging technique for encryption and decryption of remote objects. An image or object can be optically encrypted on the fly by Fresnel telescope scanning system together with an encryption key. For image decryption, the encrypted signals are received and processed with an optical coherent heterodyne detection system. The proposed method has strong performance through use of secure Fresnel telescope scanning with orthogonal polarized beams and efficient all-optical information processing. The validity of the proposed method is demonstrated by numerical simulations and experimental results.


Optimal pooling for genome re-sequencing with ultra-high-throughput short-read technologies.
New generation sequencing technologies offer unique opportunities and challenges for re-sequencing studies. In this article, we focus on re-sequencing experiments using the Solexa technology, based on bacterial artificial chromosome (BAC) clones, and address an experimental design problem. In these specific experiments, approximate coordinates of the BACs on a reference genome are known, and fine-scale differences between the BAC sequences and the reference are of interest. The high-throughput characteristics of the sequencing technology makes it possible to multiplex BAC sequencing experiments by pooling BACs for a cost-effective operation. However, the way BACs are pooled in such re-sequencing experiments has an effect on the downstream analysis of the generated data, mostly due to subsequences common to multiple BACs. The experimental design strategy we develop in this article offers combinatorial solutions based on approximation algorithms for the well-known max n-cut problem and the related max n-section problem on hypergraphs. Our algorithms, when applied to a number of sample cases give more than a 2-fold performance improvement over random partitioning.


A novel method of 3D image analysis of high-resolution cone beam CT and multi slice CT for the detection of semicircular canal dehiscence.
We investigated if current-generation computed tomographic (CT) scanners have the resolution required to objectively detect bone structure defects as small as 0.1 mm. In addition, we propose that our method is able to predict a possible dehiscence in a semicircular canal. In semicircular canal dehiscence (SCD), the bone overlying the superior canal (SC) is partially absent, causing vertigo, autophony, hyperacusis or hearing loss. Diagnosis of SCD is typically based on multi-slice computed tomography (MSCT) images combined with the consideration of clinical signs and symptoms. Recent studies have shown that MSCT tends to overestimate the size of dehiscences and may skew the diagnosis towards dehiscence when a thin bone layer remains. Evaluations of CT scans for clinical application are typically observer based. We developed a method of objectively evaluating the resolution of CT scanners. We did this for 2 types of computed tomography: MSCT, and cone beam computed tomography (CBCT), which have been reported to have a higher resolution for temporal bone scans. For the evaluation and comparison of image accuracy between different CT scanners and protocols, we built a bone cement phantom containing small, well-defined structural defects (diameter, 0.1-0.4 mm). These small inhomogeneities could reliably be detected by comparing the variances of radiodensities of a region of interest (i.e., a region containing a hole) with a homogenous region. The Fligner-Killeen test was used to predict the presence or absence of a hole (p ≥ 0.05). For our second goal, that is, to see how this technique could be applied to the detection of a possible dehiscence in a SC, a cadaveric head specimen was used to create an anatomic model for a borderline SCD; the SC was drilled to the point of translucency. After semi-automatically fitting the location of the canal, our variance-based approach allowed a clear, significant detection of the thin remaining bone layer. Our approach of statistical noise analysis on bone cement phantoms allowed us to distinguish real irregularities from measured image noise or reconstruction errors. We have shown that with computed tomography, an approach comparing radiodensity variance in regions of interest is capable of detecting inhomogeneities down to 0.1 mm (p ≤ 0.0001). Our analysis of data from the cadaveric head specimen demonstrates that this approach can be used to objectively detect thin layers of bone overlying an SC. This should provide the basis for using this approach for a semi-automated, objective detection of SCD.


Highlighting Cancer Cells with Halochromic Switches.
Halochromic coumarin-oxazine prefluorophores and targeting folate ligands can be connected covalently to the side chains of amphiphilic polymers. The resulting macromolecular constructs assemble into nanoparticles in aqueous environments. The prefluorophores do not produce any detectable fluorescence at neutral pH, but are converted into fluorophores with intense visible emission at acidic pH. Protonation opens the oxazine heterocycle to shift bathochromically the coumarin absorption and activate fluorescence with a brightness per nanoparticle approaching 5 × 105 M-1 cm-1. This value translates into a 170-fold enhancement relative to the isolated fluorophores dissolved in organic solvent. The folate ligands direct these multicomponent constructs into acidic intracellular compartments of folate-positive cells, where the prefluorophores switch to the corresponding fluorophores and produce fluorescence. The pH-induced activation of the signaling units ensures negligible background fluorescence from the extracellular matrix, which instead limits considerably the contrast accessible with model systems incorporating conventional nonactivatable fluorophores. Furthermore, no intracellular fluorescence can be detected when the very same measurements are performed with folate-negative cells. Nonetheless, control experiments demonstrate that the covalent connection of the prefluorophores to the polymer backbone of the amphiphilic constructs is essential to ensure selectivity. Model systems with prefluorophores noncovalently encapsulated cannot discriminate folate-positive from -negative cells. Thus, our structural design for the covalent integration of activatable signaling units and targeting ligands within the same nanostructured assembly together with the photophysical properties engineered into the emissive components offer the opportunity to highlight cancer cells selectively with high brightness and optimal contrast.


[Nikolaĭ Vladimirovich Timofeev-Resovskiĭ (1900-1981). (Essay on his life and works)].
The article contains a brief review of the basic works (1925-1981) written by Nikolay V. Timofeeff-Ressovsky--one of the famous geneticist of the elapsing century, the founder of radiobiology and radiation genetics, biocenology and radioecology, a prominent evolutionary biologist. In genetics, his name is associated with the development of fundamental problems of population genetics, phenogenetics, gene interaction and investigations of the role of environmental and genetic factors in expression of different characters. Timofeeff-Ressovsky classical works on mutagenesis process and especially, radiation mutagenesis, promoted penetration of methods and approaches applied in molecular physics and chemistry, into genetic analysis, and accelerated forming of the modern molecular genetics. A special place in the development of population genetics is occupied by the hypothesis of microevolutionary process developed by Nikolay V. Timofeeff-Ressovsky along with other famous biologists in the end of the 30-ies. This hypothesis connected Darwin's evolutionary theory with rapidly developing concepts of genetics. In the last years of his life, Timofeeff-Ressovsky was especially interested in a global problem which was called by him "The Biosphere and Humanity". Here was especially strikingly shown the broadness of his approach to the analysis of the biosphere phenomena in the best traditions of the Russian natural science. In the course of time, the wealth of Nikolay V. Timofeeff-Ressovsky's scientific heritage not only remains valuable, but also takes on more profundity and value.


Sexual and reproductive health literacy of school adolescents in Lao PDR.
Adolescent pregnancy in Lao PDR is the highest in Southeast Asia. It leads to negative health and social consequences in young people. It is anticipated that this problem is partly caused by limited sexual and reproductive health literacy (SRHL), leading to poor sexual and reproductive health (SRH) decisions. Based on the concept of health literacy, SRHL goes beyond knowledge and behavior and is the self-perceived ability of an individual to access the needed information, understand the information, appraise and apply the information into informed decision making for a good way to contribute to sexual and reproductive health. It is not only knowing (knowledge) and doing (behavior), but it is the process of individual's thought on an SRH problem before taking an action. The aim of this study was to measure SRHL among school-going adolescents aged 15-19 and to determine factors associated with SRHL. We conducted a cross-sectional study in rural and urban areas of Lao PDR in 2017. Respondents completed a self-administered questionnaire with five parts: socio-demographic, personal health, SRH knowledge and behavior, SRHL, and functional literacy. We calculated the SRHL score based on the HL-EU index and used descriptive statistics to determine the score and levels. Then we used bivariate statistics and multiple linear regression to identify factors associated with SRHL in these adolescents. Among 461 respondents, 65.5% had inadequate SRHL. Scores were positively and significantly associated with several factors, including: school location (β: 3.218; p<0.001), knowledge on SRH and attending SR class in school (p:0.010-p<0.001), and functional literacy on condoms, which reflected how respondents understood the use of condoms (β: 0.871; p<0.001). Because most school adolescents had inadequate SRHL, comprehensive sexual education and enabling information as well as service access for adolescents are essential to ensure that adolescents can access, understand, appraise and apply good SRH knowledge in decision-making to benefit their own health.


Removal of the Charité lumbar artificial disc prosthesis: surgical technique.
Descriptive study of a surgical technique for removal of the Charité total lumbar disc prosthesis. To describe the surgical technique to remove total disc prosthesis and the occurrence of complications in disc removal surgery. As lumbar total disc replacement seems to be more and more an accepted option to treat degenerative disc disease, the more will the need for removal increase in case of failure. Twenty-nine Charité total disc prostheses were removed in 25 consecutive patients. To avoid mobilization of the adhered great vessels away from the spine, we address L4-L5 (or higher) anterolaterally from the left side, after mobilizing the psoas and exposing the lateral side of the disc level with the prosthesis. The approach to L5-S1 is similar to the implantation of the disc prosthesis. After removal of the prosthesis, the created defect is filled with a bone graft to accomplish an anterior fusion. This retrieval surgery is always combined with a posterior pedicle screw fusion. In our series, we had 4 intraoperative major vessel lesions without major blood loss; 1 of these cases developed a deep venous thrombosis of the left leg. In 1 case, we encountered a small colon lesion and in 1 patient, a lesion of the ureter resulting in resection of the kidney. In 1 case, we had profound bleeding from the bone beneath an S1 endplate, which resulted in a total blood loss of 5100 mL. In another patient, we planned to remove the disc prosthesis; however, because of rupture of the small intestine only posterior fusion was performed. Retrieval of a Charité artificial disc prosthesis is feasible, but it has its inherent risks.