Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis.
Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism of drug effects have enabled the use of new drugs and drug combinations in rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme therapy and combined therapy with cyclosporin in rats with adjuvant arthritis. Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5 or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for a period of 40 days from the adjuvant application. Levels of serum albumin, changes in hind paw swelling and bone erosions were measured in rats as variables of inflammation and arthritis-associated destructive changes. Treatment with 5 mg of cyclosporin A, as well as with the combination therapy with cyclosporin A plus PHL, significantly inhibited both the inflammation and destructive arthritis-associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited these disease markers, although to a lesser extent and at a later stage of arthritis development. The results show the inhibitory effect of enzyme therapy on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A given in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.


High expression of survivin independently correlates with tumor progression and mortality in patients with skull base chordomas.
The object of this study was to clarify the expression characteristics and prognostic value of survivin in skull base chordomas. In this retrospective study, the authors measured the expression of survivin at the mRNA level in 81 samples from 71 patients diagnosed with skull base chordomas at their hospital in the period from July 2005 to January 2015. Clinical data collection, follow-up, and survival analyses were performed, and correlations were analyzed. Of the 71 patients, 50 had primary chordomas with a mean survivin expression level of 1.09; the other 21 patients had recurrent chordomas with a mean survivin expression level of 2.57, which was 2.36 times higher than the level in the primary chordoma patients (p < 0.001, Mann-Whitney U-test). In addition, an analysis of 18 paired samples derived from 9 patients showed that the expression level of survivin was 2.62 times higher in recurrent tumors than in primary tumors (p = 0.002, paired t-test). The Spearman rank correlation coefficient method showed that the expression level of survivin was positively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T1-weighted sequences (RT1; rs = 0.274, p = 0.021) and was negatively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T2-weighted sequences (RT2; rs = -0.389, p = 0.001). A multivariate Cox proportional-hazards model suggested that pathology (p = 0.041), survivin expression level (p = 0.018), preoperative Karnofsky Performance Status (KPS; p = 0.012), and treatment history (p = 0.009) were independent prognostic factors for tumor progression. Survivin expression level (p = 0.008), preoperative KPS (p = 0.019), tumor diameter (p = 0.027), and intraoperative blood loss (p = 0.015) were independent prognostic factors for death. Survivin expression level and preoperative KPS were independent significant prognostic factors for tumor progression and death in skull base chordoma patients. Recurrent skull base chordomas and chordomas with high RT1 and low RT2 were likely to have high survivin expression. Other independent risk factors related to tumor progression included conventional pathology and treatment history, whereas additional mortality-related risk factors included larger tumor diameter and greater intraoperative blood loss.


Lambda transducing phages for the nalA gene of Escherichia coli and conditional lethal nalA mutations.
Defective lambda transducing phages for the nalA region of the Escherichia coli chromosome were isolated from a lysogen in which lambda is inserted in the nearby glpT gene. The three classes of transducing phages designated lambdanrdA, lambdaubiG, and lambdadnalA contained bacterial DNA extending from glpT through nrdA, ubiG, and nalA, respectively. The bacterial genes are in the left arm of the lambda chromosome. Of the eleven polypeptides coded by lambdadnalA that were resolved by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate only one was not also specified by lambdadubiG. This 105,000 dalton polypeptide is the nalA gene product. The electorphoretic mobility and isoelectric point of this protein were unaffected by a nalA mutation (nalA48) that confers nalidixic acid resistance. Temperature-sensitive and amber mutations in the nalA gene were isolated using a lambdadnalA48 lysogen which is heterodiploid for nalA. The conditional lethality of these mutations proves that nalA is an essential locus.


Peptide-based topical agents and intravenous hemostat for rapid hemostasis.
Traumatic coagulopathy due to severe external injury and internal hemorrhage is life-threatening to accident victims and soldiers on the battlefield, causing considerable number of deaths worldwide. Patients with inherited bleeding disorders (such as haemophilia, von Willebrand disease, inherited qualitative platelet defects, and afibrinogenemia) also contribute to the vast number of deaths due to abnormal bleeding, and these patients are difficult to handle during surgery. Platelets and different plasma proteins play an essential role in blood coagulation and in the maintenance of the body's hemostatic balance. The improper function or deficiency of these factors cause abnormal bleeding. To address such bleeding disorders, external clotting agents (such as extracellular protein-inspired natural and synthetic peptide-based sealants and peptide-functionalized polymer/liposome-based sealants) have been developed by different groups of researchers. The primary focus of this review is to provide molecular insights into the existing biologically inspired peptide-based sealants, highlighting the advantages and limitations of such reported designed sealants to handle blood clotting, and also provide insights into the design of improved next-generation surgical sealants.


[Nasal mechanical ventilation in pediatric patients at home].
The aim of this study is to show our experience in the surveillance of home mechanical ventilation in pediatric patients. Between July 1992 and September 1996, 14 patients (20 months to 18 years of age) received home ventilation on 16 occasions. There were 10 boys and 4 girls. Home ventilation lasted from 7 days to 28 months. All patients had chronic respiratory failure secondary to neuromuscular disease, cystic fibrosis or sleep apnea syndrome. Tolerance was good in 11 patients and bad in 3, 2 of which suffered from cystic fibrosis and died in terminal respiratory failure. The patients who benefited most were those with neuromuscular disease, cyphoscoliosis and sleep apnea syndrome. The technique also has been used for ventilator weaning and as a bridge to lung transplantation. Home nasal mechanical ventilation is a useful technique for the treatment of chronic respiratory failure in adults and children.


Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U.S. and German Thyroid Cancer Group.
To determine current patterns of care and disease characteristics for patients with thyroid carcinoma, a Patient Care Evaluation Study was initiated in 1996 in the U.S. and Germany. This project addresses ongoing concerns with respect to the diagnostic evaluation and treatment of patients diagnosed with thyroid carcinoma and raises questions concerning how physicians are interpreting current standards and acting on the basis of these recommendations. Patients with primary thyroid carcinoma were entered into a prospective multicenter observational study with free choice of treatment (no control group) between January 1, 1996 and December 31, 1996 in Germany. This resulted in a total of 2537 cases under observation and analysis; 1685 patients had papillary carcinoma (66.4%), 691 had follicular carcinoma (27.2%), 70 had medullary carcinoma (2.8%), and 91 had anaplastic carcinoma (3.6%). The 2376 patients with carcinoma of either papillary or follicular histology were included in the current analysis. The major symptoms reported for patients with papillary and follicular thyroid carcinoma was neck mass (reported in 76% and 79%, respectively) followed by dysphagia (reported in 25% and 27%, respectively), stridor (reported in 9% and 14%, respectively), and neck pain (reported in 7% and 8%, respectively). Greater than 50% of the patients with papillary thyroid carcinoma were reported to have American Joint Committee on Cancer/International Union Against Cancer Stage I disease. Between 37-39% of the follicular carcinoma patients had Stage I and Stage II disease. Only slight differences in the diagnostic approach to patients with papillary or follicular carcinoma were noted. The majority of patients underwent an ultrasound of the thyroid region (78.1%), which was suggestive of carcinoma in only 39% of the cases. A thyroid scan was performed on 76.6% of patients, and the results were suggestive of carcinoma in 44.8% of the individuals. In contrast, fine-needle aspiration biopsy of the thyroid is highly recommended in the current Clinical Practice Guidelines (CPG) but results were obtained in only 27.4% of the patients. Total thyroidectomy without lymph node dissection was the most commonly used surgical procedure in the treatment of patients with papillary and follicular thyroid carcinoma. Only approximately 2% of patients at low risk in the group with Stage I disease were treated with a lobectomy. In 80% of the patients with Stage I papillary thyroid carcinoma and approximately 90% of those patients diagnosed with Stage II, III, and IV disease treating physicians chose to utilize radioiodine as adjuvant treatment after disease-directed surgery. External beam radiation was added to the treatment regimen for many patients diagnosed with Stage III and IV disease (30% in patients with papillary thyroid carcinoma and 33% in patients with follicular thyroid carcinoma). To the authors' knowledge no single effective diagnostic test for thyroid carcinoma currently is available and in the majority of cases a combination of ultrasound, thyroid scan, or fine-needle aspiration biopsy together with the clinical findings (e.g., thyroid mass) led to a diagnosis of carcinoma. The authors suspect that the high prevalence of concomitant pathologic findings such as goiter, even in the healthy population in Germany, reduces the accuracy of all diagnostic test methods and may account for the frequent use of imaging techniques. The majority of patients underwent a total or near-total thyroidectomy. Total thyroidectomy with radical lymph node dissection was used very frequently in those patients with papillary thyroid carcinoma (22%). German physicians tend to surgically treat early stage thyroid carcinoma somewhat more radically than recommended in the CPG. With respect to other treatment options employed as part of the first course of treatment, radioiodine appears to play the most important role. [See commentary o


Lactation alters the effects of conditioned stress on immune function.
During lactation, endocrine function is altered and stress responses are dampened. Stress effects on immune function are partially determined by endocrine factors; therefore, we assessed whether stress similarly alters immune function during lactation. Sprague-Dawley rats were conditioned by exposure to a tone paired with foot shock (2 sessions, 16 shocks each) prior to breeding or were left undisturbed. Lactating (day 10) (Lac) and nonlactating diestrous virgin controls (C) were killed immediately after reexposure to the tone or removal from their home cage. Plasma corticosterone stress responses were dampened in Lac relative to C animals. Peripheral blood lymphocyte proliferation to T cell receptor antibody stimulation was reduced to a similar extent in both experimental groups. Conditioned stress reduced splenocyte proliferation and increased nitrite accumulation in C animals, but not in Lac animals. Mesenteric lymph node lymphocyte proliferation was significantly increased after stress in Lac compared with C animals. Both plasma interleukin-6 (IL-6) and phytohemagglutinin-stimulated splenic IL-6 production were increased in Lac animals compared with C animals after stress exposure. These data indicate that stress-induced alterations may be determined by different regulatory mechanisms within immune compartments and that these effects depend on the physiological state of the organism.


Outcome of patients with chronic myeloid leukemia with multiple ABL1 kinase domain mutations receiving tyrosine kinase inhibitor therapy.
We investigated the impact of carrying more than one BCR-ABL1 mutation in 207 patients with chronic myeloid leukemia (102 chronic, 61 accelerated, and 44 blast phase) post-imatinib failure. Seven (8%) of 92 patients carrying mutations had more than one mutation: 4 (4%) in chronic phase, 2 (2%) in accelerated phase, and one (1 %) in blast phase. The cytogenetic response rate to second generation TKIs for patients with no, one, or more than one mutation was 88%, 69%, 50% (P=0.03) in chronic phase, 54%, 42%, 50% in accelerated phase (P=0.67), and 35%, 25%, 0% (P=0.63) in blast phase, respectively. No differences were observed in event free survival or overall survival in accelerated or blast phase according to their mutational status. However, the 4-year event free survival rates among patients in chronic phase with no, one, or more than one BCR-ABL1 mutation were 56%, 49%, and 0%, respectively (P=0.02), with overall survival rates of 91%, 69%, and 75%, respectively (P=0.13). In conclusion, patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation.


Evaluation of the Sternoclavicular Graft for the Reconstruction of Temporomandibular Joint After Gap Arthroplasty.
Ankylosis may be defined as the fusion of the articular surfaces with bony or fibrous tissue. The treatment of temporomandibular joint ankylosis poses a significant challenge because of the high incidence of recurrence. A number of interpositional materials have been used including alloplastic materials (acrylic, proplast-teflon, silastic), and autogenous tissues (temporalis muscle flaps, buccal fat pad, dermis, costochondral grafts, metatarsal, fibula, tibia, iliac crest, cranial bone and Sternoclavicular graft SCG and cartilage). Literature suggests that rather than growth centre, we need adaptive centre. SCG is presumed to be a more suitable material for interpositional arthroplasty because Sternoclavicular Joint (SCJ) and TMJ are very similar developmentally, histologically and morphologically throughout the growth period. Patients with TMJ ankylosis (8 males, 2 females) underwent release of the ankylosed joint by the senior author, between June 2013 and Novemeber 2015. The age of the patients ranged from 10 to 19 years. Pre- and post- operative assessment included a thorough history and physical examination to determine the cause of ankylosis, the maximal incisal opening, etiology and type of the ankylosis, recurrence rate. MIO at 6 months follow up was 37.4±2.633 mm (range 32-40 mm), greater than MIO achieved in immediate postoperatively {34.4±2.22 mm (range 30-38 mm). After reconstruction of temporomandibular joint with sternoclavicular graft in the growing child there was a significant increase in the growth of mandible which was stunned due to ankylosis. And the ramal height also increased. The articular reconstruction with alloplastic or autogenous grafts, or gap arthroplasty for the treatment of ankylosis is shown to be efficient in relation to the post-operative maximal incisal opening, recurrence and articular function.


The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies.
Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut-brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1 +/- 5.9 years), a 5 mm stainless-steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15 mA, 200 microseconds) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1 Hz). Two series of stimuli were applied using each stimulation frequency. Two-dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1 Hz and 1.0 Hz (P1/N2: 7.6 +/- 1.2 vs 1.4 +/- 0.3* microV, N2/P2: 17.2 +/- 1.7 vs 4.6 +/- 0.4* microV, P2/N3: 6.9 +/- 0.7 vs 4.2 +/- 0.5* microV; * = P < 0.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (P < 0.0005), with a similar trend for the P3 peak (P < 0.06), with increasing stimulus frequency from 0.1-1.0 Hz. Topographic brain maps localized the maximal early peaks (N1,P1.N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centroparietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.


Systemic lupus erythematosus with myocarditis complicating pregnancy.
We report a patient with systemic lupus erythematosus and myocarditis complicating pregnancy. Cardiomegaly and compensated congestive heart failure persisted postpartum and we had the therapeutic dilemma of a pregnancy six months later. The defined maternal prognosis of a similar disease, peripartum cardiomyopathy, suggested the need for termination of pregnancy.


PMD compensation in fiber-optic communication systems with direct detection using LDPC-coded OFDM.
The possibility of polarization-mode dispersion (PMD) compensation in fiber-optic communication systems with direct detection using a simple channel estimation technique and low-density parity-check (LDPC)-coded orthogonal frequency division multiplexing (OFDM) is demonstrated. It is shown that even for differential group delay (DGD) of 4/BW (BW is the OFDM signal bandwidth), the degradation due to the first-order PMD can be completely compensated for. Two classes of LDPC codes designed based on two different combinatorial objects (difference systems and product of combinatorial designs) suitable for use in PMD compensation are introduced.


Photodynamic therapy for 50 patients with skin cancers or precancerous lesions.
Hematoporphyrin photodynamic therapy (HpD-PDT) was used to treat 50 patients (51 lesions) with skin cancers or precancerous lesions. The preliminary results were satisfactory, with 44 cases (45 lesions) obtaining excellent results, 4 cases good, 1 case fair, and 1 case poor. The effective rate was 98%, the significant remission rate 96%, and the complete remission rate 88.2%. Exposure to sunlight should be avoided after HpD injection, since it produces photosensitivity. A follow-up for 1 to 3 years confirmed that HpD-PDT is a good new adjuvant therapy for selected cases. It brings a hopeful future to the treatment of skin cancers.


[Closing the abdominal wall - challenges and possible solutions].
The most common complications after abdominal surgery - wound infections and the development of incisional hernia - are associated with the opening and closing of the abdominal wall. Depending on the selection of patients, wound infection rates of up to 19 % and hernia rates of up to 38 % are reported. Based on a summary of the actual literature, the abdominal wall should be closed with continuous slowly absorbable sutures with a suture length to wound length ratio of over 4 using small stitches. While antiseptic suture material may help to reduce wound infections after abdominal incision, preventing the development of incisional hernia is still a unsolved problem. As there is still no standard surgical technique for abdominal wall closure, surgeons should pay greater attention to the standardisation and documentation of techniques and wound care.


Estimating adult mortality levels from information on widowhood.
Summary A range of indirect techniques has been developed for mortality estimation in societies lacking adequate vital registration records. Information on orphanhood has been widely used as an estimator of adult mortality, with generally plausible results. Doubts have remained, however, about potential biases, and the method is less satisfactory for the estimation of male mortality. Information on widowhood, or more strictly the survival of first spouse, has several possible advantages over information on orphanhood. Model first marriage functions and model life tables are used to calculate proportions widowed of first spouse, for both females and males, by marital duration and by age. These proportions widowed are then related to life table survivorship probabilities to provide weighting factors for the conversion of observed proportions widowed into estimates of survivorship probabilities. The application of the method is illustrated with data collected by the 1974 post-enumeration survey of Bangladesh, with apparently encouraging results.


[Ross-Macdonald: A model for the dengue dynamic in Cali, Colombia].
Dengue is an infection transmitted by mosquitoes and is present in all tropical and subtropical regions of the planet. In recent years, the transmission of the disease has increased, predominantly in urban and semi-urban areas, and has become an important public health problem. The National Health Institute (Instituto Nacional de Salud-INS) determined Cali to be the municipality with the most cases of dengue in Colombia. According to the INS, up to epidemiological week 18 (April 28 to May 4, 2013) 5 134 cases of dengue -and 171 cases of severe dengue- have been reported. This study presents a description of the Ross-Macdonald model, and qualitative analysis of this model, and an analysis of the sensitivity of the model to changes in its parameters. Based on the adjustment of the model obtained for cases that occurred in 2010, simulations of possible scenarios of epidemic outbreaks in the city of Cali are created and analyzed.


Integrative Genetic Approach Facilitates Precision Strategies for Acute Myocardial Infarction.
Acute myocardial infarction remains a significant cause of mortality worldwide and its burden continues to grow. Its pathophysiology is known to be complex and multifactorial, with several acquired and inherited risk factors. As advances in technology and medical therapy continue, there is now increasing recognition of the role that genetics play in the development and management of myocardial infarction. The genetic determinants of acute coronary syndrome are still vastly understudied, but the advent of whole-genome scanning and genome-wide association studies has significantly expanded the current understanding of genetics and simultaneously fostered hope that genetic profiling and gene-guided treatments could substantially impact clinical outcomes. The identification of genes associated with acute myocardial infarction can help in the development of personalized medicine, risk stratification, and improved therapeutic strategies. In this context, several genes have been studied, and their potential involvement in increasing the risk for acute myocardial infarction is being investigated. As such, this article provides a review of some of the genes potentially related to an increased risk for acute myocardial infarction as well as the latest updates in gene-guided risk stratification and treatment strategies.


Osteoclasts are not crucial for hematopoietic stem cell maintenance in adult mice.
The osteoclast is vital for establishment of normal hematopoiesis in the developing animal. However, its role for maintenance of hematopoiesis in adulthood is more controversial. To shed more light on this process, we transplanted hematopoietic stem cells from two osteopetrotic mouse models, with lack of osteoclasts or defective osteoclast function, to normal adult mice and examined the bone phenotype and hematopoiesis in the recipients. B6SJL mice were lethally irradiated and subsequently transplanted with oc/oc, Receptor Activator of Nuclear Factor Kappa B knockout or control fetal liver cells. Osteoclasts derived from the recipient animals were tested in vitro for osteoclastogenesis and resorptive function. Bone remodeling changes were assessed using biomarkers of bone turnover and micro-CT. Hematopoiesis was assessed by flow cytometry and colony formation, and hematopoietic stem cell function by secondary competitive transplantations and cell cycle analysis. After transplantation, a donor chimerism of 97-98% was obtained, and by 15 weeks mild osteopetrosis had developed in recipients of cells from osteopetrotic mice. There were no alterations in the number of bone marrow cells. Colony formation was slightly reduced in Receptor Activator of Nuclear Factor Kappa B knockout recipients but unchanged in oc/oc recipients. Phenotypically, stem cells were marginally reduced in recipients of cells from osteopetrotic mice, but no significant difference was seen in cell cycle status and in competitive secondary transplantations all three groups performed equally well. Our results indicate that osteoclast function is not crucial for hematopoietic stem cell maintenance in adult mice.


Reproductive biology of Urotrygon microphthalmum (Batoidea: Urotrygonidae) from north-eastern Brazil, tropical west Atlantic Ocean.
The reproductive biology of Urotrygon microphthalmum was studied based on specimens caught as by-catch in shrimp (Litopenaeus schmitti, Xiphopenaeus kroyeri, Farfantepenaeus subtilis and Farfantepenaeus brasiliensis) fishing operations between March 2010 and March 2012 on the coast of Pernambuco, Brazil. Females reached a larger total length (LT ) and total body mass (MT ) (298 mm and 148 g) than males (250 mm and 90 g). Length at maturity was estimated to be 188 and 199 mm LT for males and females. Uterine fecundity ranged from one to four embryos (mean ± s.d.: 1·85 ± 0·45). Size at birth was estimated to be 105 mm LT . Gestation lasted between 4 and 5 months. The reproductive cycle of U. microphthalmum is hypothesized to be asynchronous and biannual.


"It's for a good cause, isn't it?" - Exploring views of South African TB research participants on sample storage and re-use.
The banking of biological samples raises a number of ethical issues in relation to the storage, export and re-use of samples. Whilst there is a growing body of literature exploring participant perspectives in North America and Europe, hardly any studies have been reported in Africa. This is problematic in particular in light of the growing amount of research taking place in Africa, and with the rise of biobanking practices also on the African continent. In order to investigate the perspectives of African research participants, we conducted a study with research participants in a TB study in the Western Cape, South Africa. Semi-structured interviews were conducted using an interview guide which drew on the most prominent themes expressed in current literature on sample storage, re-use and exportation. Interviews were conducted in Afrikaans and subsequently translated into English by the same interviewer. Interviews were transcribed verbatim and analysed qualitatively. The results of our study indicate that the majority of participants were supportive of giving one-time consent to the storage and re-use of their samples. The concept of research being for a "good cause" was a central prerequisite. Additionally, a significant minority requested that they be re-contacted if a future use was not stipulated on the original consent. There was also considerable variation in how participants understood the concept of a 'good cause', with participants describing three distinct categories of research, of which two were generally thought to constitute 'good cause' research. Research that was for-profit was considered to fall outside the spectrum of 'good cause' research. Participants displayed confidence in the abilities of the researchers to make future decisions regarding sample use, but seemed unaware of the role of ethics committees in either this process or more generally. Participants expressed a wide and complex range of views about issues of sample storage and re-use, and they showed a great deal of trust in researchers. Participants' willingness to have their samples stored and re-used is consistent with findings from existing studies. However, in contrast to existing literature, participants were generally not in favour of for-profit research. Further research needs to be done to explore these ideas in other communities, both in South Africa and other countries.


The application of functional MRI of memory in temporal lobe epilepsy: a clinical review.
Functional MRI (fMRI) is a useful tool for noninvasively localizing areas in the brain involved in specific cognitive functions. Since its introduction, there has been considerable speculation regarding the role it may play in the presurgical assessment of temporal lobe epilepsy (TLE). This review considers the progress made to date in using fMRI to investigate memory processing in the medial temporal lobe in normal subjects and in those with TLE. Results so far suggest that fMRI will be incorporated into the presurgical assessment of TLE in the coming years to improve definition of eloquent cerebral areas, with the objective of minimizing the adverse cognitive sequelae of anterior temporal lobe resection.


A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic renal cell carcinoma.
Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau (VHL) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides. Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock. Four out of five evaluable patients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively. The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. 98C0139.


Improving DNA vaccines targeting viral infection.
DNA vaccination techniques have been recently under intensive investigation both preclinically and in human studies aimed at impacting viral infection. Collectively, DNA vaccines expressing viral antigens induce both antigen-specific humoral and cellular immune responses which in model systems are capable of impacting viral infection. However, in clinical settings the potency of this approach is still under investigation. Efficacy is improved in specific circumstances through the addition of immunomodulatory molecules including cytokines as plasmid cassettes or through modification of the numbers of specific CpG sequences present in the backbone. Furthermore, combined vaccination schemes have been an important research focus for generating enhanced immunogenicity against viral infections. The ultimate utility of these approaches to prevent viral infection will require more work. However, improvements in the potency and focus of DNA vaccines present us with new opportunities for both basic research into protective immunity as well as novel strategies for immune therapy and prophylaxis.


Impact of treatment time on the survival of patients suffering from invasive fungal rhinosinusitis.
Invasive fungal rhinosinusitis is an uncommon disease with high mortality rates. There is currently no consensus on the best treatment timing. We studied the impact of the treatment timing on the survival of patients experiencing invasive fungal rhinosinusitis. We conducted a retrospective study of patients suffering from invasive fungal rhinosinusitis. The duration of symptoms, clinical presentations, clinical signs, diagnoses, treatments, and outcomes were collected. It was observed that more than 70% of the mortalities occurred within the subgroup of patients who exhibited symptoms of the disease within 14 days before admission. After adjusting for the confounders, the time taken to treat the patients was the most statistically significant predictor for mortality (P = 0.045). We found no significant relationships between mortality and its significant covariates, which included the underlying diseases (P = 0.91) or complications (P = 0.55). Our study demonstrates that the time taken to treat the patients is an important determinant for the survival of patients who are afflicted with invasive fungal rhinosinusitis. The appropriate treatments should be administered within 14 days from the time the symptoms begin to manifest.


The structure of tartar-emetic.
Evaluation of the validity of the different formulae assigned to tarar-emetic is reviewed. According to the recent and most valid structure, tartar emetic is defined as potassium hydroxytartratoantimonite hemihydrate which is a derivative of the antimonite ion [Sb(OH)4]-.


Prevention of Parent to Child Transmission of HIV: Single Centre Experience of 14 years at Tertiary Care Hospital in Delhi, India.
Prevention of Parent To Child Transmission (PPTCT) of HIV/AIDS is an integral component of AIDS control programme. PPTCT is an ongoing programme since last 15 years. The aim of the study was to evaluate the reduction in the burden of disease in newborn and infants by prevention of parents to child transmission of HIV/AIDS. This retrospective study was conducted at Department of Obstetrics and Gynecology in a tertiary care hospital of Delhi from May 2002 to May 2015. The data was collected from records of maternal details registered at PPTCT clinic as well as list of infants undergoing Early Infant Diagnosis (EID) recorded in the standard format as per instructions from National AIDS Control Organization (NACO) of India. The Programme performance was assessed against performance indicators stated by NACO, India. Evaluation was done by dividing study period into two halves of seven years each. Out of 2,52,447 new antenatal case registration, overall, 43% received pretest of which, 91% were tested. Antenatal seropositivity rate varied from 0.1%-0.25%. Of 243 seropositive antenatal women 187 partners tested positive. While 25 women opted for MTP, 15 had still births. There were 17 neonatal deaths at 3-12 months attributable to respiratory infections and diarrheal diseases. Operative delivery rates declined from 50% to 31% over the years. Most women opted for breast feeding. The lost to follow up rate of newborns was quite high with details of only 43.5% being available at 18 months of infant's age. A total of three infants tested HIV positive at 18 months of age. The study highlights the practical aspects of policy implementation and operational issues involved in low resource country.


Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid.
Single-cell RT-PCR was used to sample CD19(+) B cell repertoires in cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) or viral meningitis. Analysis of amplified Ab H and L chain products served to identify the rearranged germline segment and J segment, and to determine the degree of homology for the H and L chain sequence of individual B cells. The B cell repertoire of viral meningitis CSF was predominantly polyclonal, whereas B cell clonal expansion was a prominent feature of the IgG repertoire in three of four MS patients. Two dominant clonal populations in one MS CSF accounted for approximately 70% of the IgG H chain V regions sequenced, while the corresponding IgM repertoires were more heterogeneous. One clonal B cell population revealed multiple L chain rearrangements, raising the possibility of a role for receptor editing in shaping the B cell response in some MS patients. The most immediate implications of identifying rearranged Ig sequences in MS B cells is the potential to accurately recreate recombinant Abs from these overrepresented H and L chains that can be used to discover the relevant Ag(s) in MS.


Impact and Beneficial Critical Points of Clinical Outcome in Corticosteroid Management of Adult Patients With Sepsis: Meta-Analysis and GRADE Assessment.
Background: With new randomised pieces of evidence and the latest clinical practice guideline from the BMJ emerging in 2018, an updated analysis of best available evidence on the controversial effects of corticosteroids in sepsis is warranted. Objectives: To comprehensively evaluate whether corticosteroids are beneficial in reducing mortality and what cumulative dosage, daily dosage, and duration of corticosteroid treatment would enable adult patients with sepsis to reach the critical point of benefits. Methods: Ovid MEDLINE, Ovid EMbase, Cochrane Library, and LILACS database were searched until March 22, 2019. Results: Thirty RCTs with 8,836 participants were identified. Long course low-dose corticosteroid therapy could improve 28-day mortality (RR = 0.90, 95% CI = 0.84-0.97; high quality), intensive care unit mortality (RR = 0.87; 95% CI = 0.79-0.95; moderate quality), and in-hospital mortality (RR = 0.88, 95% CI = 0.79-0.997; high quality). However, we found no benefits for 90-day, 180-day, and 1-year mortality. Subgroup results of long course corticosteroid treatment in a population with septic shock and vasopressor-dependent septic shock, corticosteroid regimen with hydrocortisone plus fludrocortisone, corticosteroid dosing strategies including bolus dosing and infusion dosing, the strategies of abrupt discontinuation, timing of randomisation ≤24 h, impact factor of ≥10, and sample size ≥500 were associated with a marginally reduction in 28-day mortality. Conclusions: This meta-analysis found that the long course low-dose and not short course high-dose corticosteroid treatment could marginally improve short-term 28-day mortality with high quality, especially septic shock and vasopressor-dependent septic shock, and it is recommended that long course (about 7 days) low-dose (about 200-300mg per day) hydrocortisone (or equivalent) with cumulative dose (at least about 1,000mg) may be a viable management option for overall patients with sepsis, and it can be also adapted to patient with septic shock alone. Early hydrocortisone plus fludrocortisone administration, via continuous infusion or bolus dosing, is also particularly important for the prognosis. Abrupt discontinuation of corticosteroids, as opposed to the conventional tapered discontinuation, may be considered as a desirable option in 28-day mortality. The safety profile of long course low-dose corticosteroid treatment, including adverse hyperglycaemia and hypernatraemia events, remains a concern, although these events could be easily treated. Clinical Trial Registration: PROSPERO, identifier CRD 42018092849.


Macplocimine A, a new 18-membered macrolide isolated from the filamentous sulfur bacteria Thioploca sp.
Macplocimine A (1), a rare naturally occurring 18-membered macrolide, was isolated from the marine-derived filamentous sulfur bacteria Thioploca sp. The structure was determined by a combination of spectroscopic techniques, including HRESIMS, 1D and 2D NMR analyses. 1 features a thymine group, which is attached to an aromatic fused 18-membered macrolide ring structure derived from a polyketide synthase biosynthetic pathway.


Sensory hypoinnervation in club foot.
We have compared the density of nerve fibres in the synovium in club foot with that of specimens obtained from the synovium of the hip at operations for developmental dysplasia. The study focused on the sensory neuropeptides substance P; calcitonin gene-related peptide; protein gene product 9.5, a general marker for mature peripheral nerve fibres; and growth associated protein 43, a neuronal marker for new or regenerating nerve fibres. In order to establish whether there might be any inherent difference we analysed the density of calcitonin gene-related peptide-positive nerve fibres in the hip and ankle joints in young rats. Semi-quantitative analysis showed a significant reduction in the number of sensory and mature nerve fibres in the synovium in club foot compared with the control hips. Calcitonin gene-related peptide (CGRP) positive fibres were reduced by 28%, substance P-positive fibres by 36% and protein gene product 9.5-positive fibres by 52% in club foot. The growth associated protein 43-positive fibres also seemed to be less in six samples of club foot. No difference in the density of CGRP-positive nerve fibres was observed in the synovium between ankle and hip joints in rats. The lack of sensory input may be responsible for the fibrosis and soft-tissue contractures associated with idiopathic club foot.


An analysis of reasons for discontinuing participation in a practice-based research network.
Now that primary care practice-based research networks are known to be feasible, it is important to learn more about the reasons practices participate and withdraw. The Ambulatory Sentinel Practice Network (ASPN) experience presents a special opportunity to study 32 practices that withdrew from the Network since it began in 1982. One hundred percent of these practices responded to a structured telephone survey. The desire to be part of a group doing research (47%) and response to recruitment by an esteemed colleague (28%) were the most important reasons for joining the Network. Changes within the practice (50%), the additional burdens associated with ASPN (22%), and lack of support among practice colleagues and staff (13%) were the most important reasons for withdrawing. Six suggestions were made that could have helped these practices continue in ASPN. Thirteen percent of practices that withdrew rejoined the Network at a later date. Eight years after initiating investigations, 70% of the practices that were ever part of ASPN remained fully involved.


Overexpression of Mst1 reduces gastric cancer cell viability by repressing the AMPK-Sirt3 pathway and activating mitochondrial fission.
Mammalian sterile 20-like kinase 1 (Mst1) plays a critical role in regulating cell survival and apoptosis. However, its influence on gastric cancer cell viability is not understood. Our study aims to explore the specific role of Mst1 in gastric cancer. Cellular viability was measured via TUNEL staining, MTT assays, and Western blotting. Immunofluorescence was performed to observe mitochondrial fission. Mst1 overexpression assays were conducted to observe the regulatory mechanisms of Mst1 in mitochondrial fission and cell apoptosis. The results demonstrated that Mst1 was downregulated in AGS cells when compared with GES-1 cells. However, overexpression of Mst1 reduced cell viability and increased apoptosis in AGS cells. Molecular experiments showed that Mst1 overexpression mediated mitochondrial damage, as evidenced by decreased ATP production, increased ROS generation, more cyt-c translocation from the mitochondria into the cytoplasm and nucleus, and activated the caspase-9-related apoptotic pathway. Furthermore, we found that mitochondrial fission was required for Mst1-induced mitochondrial dysfunction; inhibition of mitochondrial fission sustained mitochondrial homeostasis in response to Mst1 overexpression. In addition, our data revealed that Mst1 controlled mitochondrial fission via repressing the AMPK-Sirt3 pathway. Activation of the AMPK-Sirt3 pathway negated the promoting effect of Mst1 overexpression on mitochondrial fission. Altogether, our data identified Mst1 as a novel tumor-suppressive factor in promoting cell death in gastric cancer cells by triggering mitochondrial fission and blocking the AMPK-Sirt3 axis.


Structural and mechanistic studies of bis(phenolato)amine zinc(II) catalysts for the polymerization of epsilon-caprolactone.
The syntheses, characterization, epsilon-caprolactone (CL) polymerization activity, and kinetics investigation of two zinc(II) bis(phenolato)amine complexes L2Zn2 are reported (L = methylamino-N,N-bis(2-methylene-4,6-di-tert-butylphenolato) and/or methylamino-N,N-bis(2-methylene-4-adamantyl-6-tert-butylphenolato)). X-ray crystallographic and 1H NMR studies, including NOESY and PGSE experiments, provided insight into the solid and solution state structures, respectively, as well as evidence for the catalytically active species responsible for the ring-opening polymerization of CL. Additionally, solution polymerizations and kinetic experiments involving (L1)2Zn2 in the presence of benzyl alcohol (BnOH) were performed to elucidate the influence of catalyst structure, solvent, and the concentration dependence of the catalytically active species, CL, and BnOH on the rate and control of poly-epsilon-caprolactone (PCL) formation. The structural, polymerization, and kinetic data support equilibria involving both mononuclear and dinuclear forms of (L1)2Zn2 as well as a monomer-activated route to PCL.


[Research on investing methods and mold cooling methods of the self-made investment for pure titanium castings].
To observe the influence of different investing methods and mold cooling methods on pure titanium castings invested in the self-made investment, and to provide theoretic base for the development for the investment. The influence of investing methods (one-step investing method and two-step investing method) on castability and crown fit of titanium castings were investigated, and the influence of cooling methods on reaction layers, mechanical properties and crown fit of titanium castings were investigated. Both the investing methods exhibited good castability, but only the titanium full crowns by one-step investing method showed clinically acceptable fit. Although the quenching group showed thinner reaction layer(100 microm), lower strength and similar elongation rate, the titanium castings by bench cooling showed clinically acceptable full crown fit with 115 microm thick reaction layer as cast. The one-step investing method and the bench cooling are recommended for the self-made investment.


Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra.
The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote survival and differentiation of midbrain dopaminergic (DAergic) neurons in vitro and in vivo. This is consistent with their expression and that of their cognate receptors, trkB and trkC, in the nigrostriatal system. Degeneration of DAergic neurons of the substantia nigra and alpha-synuclein-positive aggregates in the remaining substantia nigra (SN) neurons are hallmarks of Parkinson's disease (PD). Reduced expression of BDNF has been reported in the SN from PD patients. Moreover, mutations in the BDNF gene have been found to play a role in the development of familial PD. We show now that haploinsufficiencies of the neurotrophin receptors trkB and/or trkC cause a reduction in numbers of SN neurons in aged (21-23 month old) mice, which is accompanied by a reduced density in striatal tyrosine hydroxylase immunoreactive (TH-ir) fibers. These aged mutant mice, in contrast to wild-type littermates, display an accumulation of alpha-synuclein in the remaining TH-positive neurons of the SN. We conclude that impairment in trkB and/or trkC signaling induces a phenotype in the aged SN, which includes two hallmarks of PD, losses of TH positive neurons and axons along with massive neuronal deposits of alpha-synuclein.


[Laparoscopic cholecystectomy as a same-day surgical procedure].
The aim of this study was to describe the results of laparoscopic cholecystectomy as an outpatient procedure in a prospective, consecutive, descriptive study. The study included 50 patients selected in the period from April to December 1997, who accepted the outpatient procedure. Preoperative complications, morbidity during hospital stay, length of hospital stay, frequency of readmission and the satisfaction of the patients were registered. In our investigation we found a risk of preoperative complications of 6% (severe 0%), a morbidity during hospital stay of 6% (severe 2%) and an incidence of readmission of 4%. A total of 74% of the patient went home on the same day as the procedure, and 90% of all patients had been discharged 24 hours later. The patients showed a high degree of satisfaction. In conclusion laparoscopic cholecystectomy as an outpatient procedure may be performed with a low risk of complications, a low incidence of readmission, a high degree of satisfaction in patients, but with a high frequency of primary admission (26%).


WoCoVA consensus on the clinical use of in-line filtration during intravenous infusions: Current evidence and recommendations for future research.
The need for filtering intravenous infusions has long been recognized in the field of venous access, though hard scientific evidence about the actual indications for in-line filters has been scarce. In the last few years, several papers and a few clinical studies have raised again this issue, suggesting that the time has come for a proper definition of the type of filtration, of its potential benefit, and of its proper indications in clinical practice. The WoCoVA Foundation, whose goal is to increase the global awareness on the risk of intravenous access and on patients' safety, developed the project of a consensus on intravenous filtration. A panel of experts in different aspects of intravenous infusion was chosen to express the current state of knowledge about filtration and to indicate the direction of future research in this field. The present document reports the final conclusions of the panel.


B-type natriuretic peptide is an independent predictor of endothelial function in man.
BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH.


Current and emerging treatment modalities for metastatic castration-resistant prostate cancer.
Docetaxel-based therapy is established as the standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from two landmark Phase III studies. However, prognosis remains poor, with a median survival of less than 2 years. There is no standard of care for patients who progress during or after docetaxel treatment, which represents a real unmet medical need. Several small retrospective studies suggest that patients with mCRPC who responded to first-line docetaxel-based therapy are sensitive to re-treatment, but a survival benefit in prospective randomized trials has not been demonstrated. Epithelial-stromal interactions in the tumour microenvironment appear to play a central role in prostate cancer progression and response to therapy. Recent insights into the molecular mechanisms that underpin prostate cancer progression have allowed the identification of potential therapeutic targets. New agents, including angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines and immunotherapies are currently undergoing clinical development in advanced prostate cancer using docetaxel as a backbone. Several Phase III studies have now been completed. Sipuleucel-T prolonged survival compared with placebo in asymptomatic or minimally symptomatic patients with mCRPC. Cabazitaxel plus prednisone prolonged survival in patients with mCRPC who progressed during or after docetaxel-based therapy compared with the active agent mitoxantrone, plus prednisone. Multidisciplinary management and optimization of the role and timing of new agents in this evolving treatment continuum will be critical to maximizing patient outcomes. Identification of predictive markers and better gene expression profiling will be critical to tailoring therapies to individual patients and disease states, whereas validated surrogate markers of overall survival will help accelerate drug approval.


The race to save lives: demonstrating the use of social media for search and rescue operations.
Utilizing social media in an emergency can enhance abilities to locate and evacuate casualties more rapidly and effectively, and can contribute towards saving lives following a disaster, through better coordination and collaboration between search and rescue teams. An exercise was conducted in order to test a standard operating procedure (SOP) designed to leverage social media use in response to an earthquake, and study whether social media can improve joint Israeli-Jordanian search and rescue operations following a regional earthquake. First responders from both Jordan and Israel were divided into two mixed groups of eight people each, representing joint (Israeli-Jordanian) EMS teams. Simulated patients were dispersed throughout the Ben-Gurion University Campus. The first search and rescue team used conventional methods, while the second team also used social media channels (Facebook and Twitter) to leverage search and rescue operations. Eighteen EMS and medical professionals from Israel and Jordan, which are members of the Emergency Response Development and Strategy Forum working group, participated in the exercise. The social media team found significantly more mock casualties, 21 out of 22 (95.45%) while the no-media team found only 19 out of 22 (86.36%). Fourteen patients (63.63%) were found by the social media team earlier than the no-media team. The differences between the two groups were analyzed using the Mann-Whitney U-test, and evacuation proved to be significantly quicker in the group that had access to social media. The differences between the three injury severities groups' extraction times in each group were analyzed using the Kruskal-Wallis test for variance. Injury severity influenced the evacuation times in the social media team but no such difference was noted in the no-media team. Utilizing social media in an emergency situation enables to locate and evacuate casualties more rapidly and effectively. Social media can contribute towards saving lives during a disaster, in national and bi-national circumstances. Due to the small numbers in the groups, this finding requires further verification on a larger study cohort.


Crustal architecture of the cascadia forearc.
Seismic profiling data indicate that the thickness of an accreted oceanic terrane of Paleocene and early Eocene age, which forms the basement of much of the forearc beneath western Oregon and Washington, varies by approximately a factor of 4 along the strike of the Cascadia subduction zone. Beneath the Oregon Coast Range, the accreted terrane is 25 to 35 kilometers thick, whereas offshore Vancouver Island it is about 6 kilometers thick. These variations are correlated with variations in arc magmatism, forearc seismicity, and long-term forearc deformation. It is suggested that the strength of the forearc crust increases as the thickness of the accreted terrane increases and that the geometry of the seaward edge of this terrane influences deformation within the subduction complex and controls the amount of sediment that is deeply subducted.


Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder.
Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder.


Tenofovir-based antiretroviral therapy in HBV-HIV coinfection: results from the TREAT Asia HIV Observational Database.
The World Health Organization recommends HBV-HIV-coinfected individuals start antiretroviral therapy containing tenofovir. Here we describe first-line tenofovir use and treatment outcomes in coinfected patients in Asia. HBV surface antigen positive patients enrolled in the TREAT Asia HIV Observational Database who started first-line antiretroviral therapy were included. Logistic regression adjusted for period of treatment initiation was used to determine factors associated with tenofovir use. Generalized estimating equations were used to evaluate factors associated with alanine transaminase levels and CD4(+) T-cell count on treatment. There were 548 eligible patients, of whom 149 (27.2%) started tenofovir. Patients treated in high/high-middle income countries (odds ratio 4.4 versus low/low-middle, 95% CI 2.6, 7.4; P<0.001) and those with elevated baseline alanine transaminase (odds ratio 4.2 versus normal, 95% CI 2.4, 7.2; P<0.001) were more likely to receive tenofovir. Hepatitis C antibody positive patients (odds ratio 0.4 versus negative, 95% CI 0.2, 0.8; P=0.008) were less likely. In those starting antiretroviral therapy with elevated alanine transaminase, mean reduction after tenofovir initiation was 11.2 IU/l (95% CI 0.9, 21.6; P=0.034) lower compared with those using a non-tenofovir-based regimen although this did not significantly increase the chance of alanine transaminase normalization. Tenofovir use was not associated with a superior CD4(+) T-cell response. HBV-HIV-coinfected patients in Asia are most likely to receive tenofovir if they are treated in a high/high-middle income country, have elevated alanine transaminase levels and are hepatitis C antibody negative. Compared to other antiretroviral therapies, tenofovir-based regimens more effectively reduce liver inflammation in HBV-HIV-coinfection but do not result in superior CD4(+) T-cell recovery.


Harnessing Machine Intelligence in Automatic Echocardiogram Analysis: Current Status, Limitations, and Future Directions.
Echocardiography (echo) is a critical tool in diagnosing various cardiovascular diseases. Despite its diagnostic and prognostic value, interpretation and analysis of echo images are still widely performed manually by echocardiographers. A plethora of algorithms has been proposed to analyze medical ultrasound data using signal processing and machine learning techniques. These algorithms provided opportunities for developing automated echo analysis and interpretation systems. The automated approach can significantly assist in decreasing the variability and burden associated with manual image measurements. In this paper, we review the state-of-the-art automatic methods for analyzing echocardiography data. Particularly, we comprehensively and systematically review existing methods of four major tasks: echo quality assessment, view classification, boundary segmentation, and disease diagnosis. Our review covers three echo imaging modes, which are B-mode, M-mode, and Doppler. We also discuss the challenges and limitations of current methods and outline the most pressing directions for future research. In summary, this review presents the current status of automatic echo analysis and discusses the challenges that need to be addressed to obtain robust systems suitable for efficient use in clinical settings or point-of-care testing.


Implementation of the Comprehensive Unit-Based Safety Program to Improve Infection Prevention and Control Practices in Four Neonatal Intensive Care Units in Pune, India.
Objective: To implement the Comprehensive Unit-based Safety Program (CUSP) in four neonatal intensive care units (NICUs) in Pune, India, to improve infection prevention and control (IPC) practices. Design: In this quasi-experimental study, we implemented CUSP in four NICUs in Pune, India, to improve IPC practices in three focus areas: hand hygiene, aseptic technique for invasive procedures, and medication and intravenous fluid preparation and administration. Sites received training in CUSP methodology, formed multidisciplinary teams, and selected interventions for each focus area. Process measures included fidelity to CUSP, hand hygiene compliance, and central line insertion checklist completion. Outcome measures included the rate of healthcare-associated bloodstream infection (HA-BSI), all-cause mortality, patient safety culture, and workload. Results: A total of 144 healthcare workers and administrators completed CUSP training. All sites conducted at least 75% of monthly meetings. Hand hygiene compliance odds increased 6% per month [odds ratio (OR) 1.06 (95% CI 1.03-1.10)]. Providers completed insertion checklists for 68% of neonates with a central line; 83% of checklists were fully completed. All-cause mortality and HA-BSI rate did not change significantly after CUSP implementation. Patient safety culture domains with greatest improvement were management support for patient safety (+7.6%), teamwork within units (+5.3%), and organizational learning-continuous improvement (+4.7%). Overall workload increased from a mean score of 46.28 ± 16.97 at baseline to 65.07 ± 19.05 at follow-up (p < 0.0001). Conclusion: CUSP implementation increased hand hygiene compliance, successful implementation of a central line insertion checklist, and improvements in safety culture in four Indian NICUs. This multimodal strategy is a promising framework for low- and middle-income country healthcare facilities to reduce HAI risk in neonates.


White Spot Syndrome Virus Benefits from Endosomal Trafficking, Substantially Facilitated by a Valosin-Containing Protein, To Escape Autophagic Elimination and Propagate in the Crustacean Cherax quadricarinatus.
As the most severely lethal viral pathogen for crustaceans in both brackish water and freshwater, white spot syndrome virus (WSSV) has a mechanism of infection that remains largely unknown, which profoundly limits the control of WSSV disease. By using a hematopoietic tissue (Hpt) stem cell culture from the red claw crayfish Cherax quadricarinatus suitable for WSSV propagation in vitro, the intracellular trafficking of live WSSV, in which the acidic-pH-dependent endosomal environment was a prerequisite for WSSV fusion, was determined for the first time via live-cell imaging. When the acidic pH within the endosome was alkalized by chemicals, the intracellular WSSV virions were detained in dysfunctional endosomes, resulting in appreciable blocking of the viral infection. Furthermore, disrupted valosin-containing protein (C. quadricarinatus VCP [CqVCP]) activity resulted in considerable aggregation of endocytic WSSV virions in the disordered endosomes, which subsequently recruited autophagosomes, likely by binding to CqGABARAP via CqVCP, to eliminate the aggregated virions within the dysfunctional endosomes. Importantly, both autophagic sorting and the degradation of intracellular WSSV virions were clearly enhanced in Hpt cells with increased autophagic activity, demonstrating that autophagy played a defensive role against WSSV infection. Intriguingly, most of the endocytic WSSV virions were directed to the endosomal delivery system facilitated by CqVCP activity so that they avoided autophagy degradation and successfully delivered the viral genome into Hpt cell nuclei, which was followed by the propagation of progeny virions. These findings will benefit anti-WSSV target design against the most severe viral disease currently affecting farmed crustaceans.IMPORTANCE White spot disease is currently the most devastating viral disease in farmed crustaceans, such as shrimp and crayfish, and has resulted in a severe ecological problem for both brackish water and freshwater aquaculture areas worldwide. Efficient antiviral control of WSSV disease is still lacking due to our limited knowledge of its pathogenesis. Importantly, research on the WSSV infection mechanism is also quite meaningful for the elucidation of viral pathogenesis and virus-host coevolution, as WSSV is one of the largest animal viruses, in terms of genome size, that infects only crustaceans. Here, we found that most of the endocytic WSSV virions were directed to the endosomal delivery system, strongly facilitated by CqVCP, so that they avoided autophagic degradation and successfully delivered the viral genome into the Hpt cell nucleus for propagation. Our data point to a virus-sorting model that might also explain the escape of other enveloped DNA viruses.


Effects of Nanoclay and Silica Flour on the Mechanical Properties of Class G Cement.
The mechanical properties of oil well cement slurry are usually measured to evaluate the durability, sustainability, and long-lasting behavior of a cement sheath under wellbore conditions. High-pressure and high-temperature (HPHT) conditions affect the mechanical properties of cement slurry such as its strength, elasticity, and curing time. In this study, an organically modified montmorillonite nanoclay (NC) and silica flour (SF) materials are used to enhance the strength of the class G cement. Four different cement slurries with the addition of different concentrations of NC (1% and 2%) and SF (20%) in a class G cement were tested under temperatures ranging between 70 and 100 °C and pressure ranging between 1000 and 3000 psia. The slurries were prepared by maintaining a water to cement ratio of 0.44. All the slurries were cured for 24 h before any test was conducted. Extensive laboratory experiments were carried out to measure the compressive and tensile strength of cement slurries cured at HPHT conditions. Compressive strength was measured using unconfined compressive strength (UCS) tests, scratch tests, and ultrasonic cement analyzer (UCA). Tensile strength was measured using breakdown pressure tests and Brazilian disc test analysis. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and petrophysical analysis were also carried out to evaluate the performance of new cement additives at HPHT conditions. Results showed that the addition of organically modified NC and SF significantly increased the compressive and tensile strength of the class G cement slurry cured at HPHT conditions.


[Pathology of breast tumors occurring before the age of 30 in Brazzaville].
In 42 months, 175 patients (171 women and 4 men) were followed for mammary tumor in the Department of Medicine and Cancerology of l'Hopital General of Brazzaville. Among them, 63 files were retained for the study, corresponding to women under the age of 30. The study of these cases enabled the authors to establish the relatively important frequency of large tumors (larger than 5 cm), and the similarity of the general aspects of the pathology of mammary tumors, as compared to european studies.


Benefit of Mohs Micrographic Surgery Over Wide Local Excision for Melanoma of the Head and Neck: A Rational Approach to Treatment.
There are limited published data comparing wide local excision (WLE) with Mohs micrographic surgery (MMS) for the treatment of melanoma. To describe a novel treatment algorithm for the surgical management of head and neck melanoma and compare rates of local recurrence for tumors treated with either MMS using immunohistochemistry or WLE. A 10-year retrospective chart review including all in situ and invasive melanomas of the head and neck treated at one institution from January 2004 to June 2013. Among 388 patients with melanoma, MMS was associated with decreased rates of local recurrence (p = .0012). However, patient and tumor characteristics varied significantly, and WLE subgroup was largely composed of higher stage and risk tumors. Subgroup analysis found that patients with in situ or thin invasive tumors (<0.8 mm) treated with MMS had improved local recurrence outcomes (p = .0049), despite more frequent tumor location on high risk anatomic sites (e.g., central face). In addition, MMS was associated with a favorable delay in time to local recurrence among in situ tumors (HR = 31.8; p = .0148). These findings further support the use of MMS for treatment of melanoma of the head and neck and help to validate our proposed clinical decision tree.


Personalized Prognostic Prediction Models for Breast Cancer Recurrence and Survival Incorporating Multidimensional Data.
In this study, we developed integrative, personalized prognostic models for breast cancer recurrence and overall survival (OS) that consider receptor subtypes, epidemiological data, quality of life (QoL), and treatment. A total of 15 314 women with stage I to III invasive primary breast cancer treated at The University of Texas MD Anderson Cancer Center between 1997 and 2012 were used to generate prognostic models by Cox regression analysis in a two-stage study. Model performance was assessed by calculating the area under the curve (AUC) and calibration analysis and compared with Nottingham Prognostic Index (NPI) and PREDICT. Host characteristics were assessed for 10 809 women as the discovery population (median follow-up = 6.09 years, 1144 recurrence and 1627 deaths) and 4505 women as the validation population (median follow-up = 7.95 years, 684 recurrence and 1095 deaths). In addition to the known clinical/pathological variables, the model for recurrence included alcohol consumption while the model for OS included smoking status and physical component summary score. The AUCs for recurrence and OS were 0.813 and 0.810 in the discovery and 0.807 and 0.803 in the validation, respectively, compared with AUCs of 0.761 and 0.753 in discovery and 0.777 and 0.751 in validation for NPI. Our model further showed better calibration compared with PREDICT. We also developed race-specific and receptor subtype-specific models with comparable AUCs. Racial disparity was evident in the distributions of many risk factors and clinical presentation of the disease. Our integrative prognostic models for breast cancer exhibit high discriminatory accuracy and excellent calibration and are the first to incorporate receptor subtype and epidemiological and QoL data.


Pulmonary Hemorrhage Following Percutaneous Computed Tomography-Guided Lung Biopsy: Retrospective Review of Risk Factors, Including Aspirin Usage.
To evaluate the significance of aspirin, as well as, other potential confounding risk factors, on the incidence and volume of pulmonary hemorrhage in patients undergoing percutaneous computed tomography-guided lung biopsy. This retrospective study was approved by the institutional review board. Between September 2013 and December 2014, 252 patients taking aspirin underwent transthoracic computed tomography-guided lung biopsy. Patient, technical, and lesion-related risk factors were evaluated. Univariate analysis was performed with a Student's t test, chi-square test, or Fisher's exact test, as appropriate followed by multivariate logistic regression. Of 252 patients, 49 (19.4%) continued or stopped aspirin ≤4 days prior to biopsy and 203 (80.6%) patients stopped aspirin ≥5 days prior to biopsy. Pulmonary hemorrhage occurred in 174 cases (69.0%). The median volume of hemorrhage was 3.74 cm3 (range, 0-163.5 cm3). Multivariate analysis revealed that lesion size (P < 0.0001) and lesion depth (P < 0.0001) were independent risk factors for the incidence of pulmonary hemorrhage, while lesion size (P = 0.0035), transgression of intraparenchymal vessels (P < 0.0001), and lesion depth (P = 0.0047) were independent risk factors for severity of hemorrhage. Aspirin stopped ≤4 days from a percutaneous lung biopsy was not associated with pulmonary hemorrhage. Aspirin taken concurrently or stopped within 4 days of transthoracic lung biopsy is not an independent risk factor for pulmonary hemorrhage. The incidence of hemorrhage following lung biopsy is associated with lesion size and depth, while the severity of hemorrhage is associated with lesion size, depth, as well as traversal of intraparenchymal vessels.


Oculomotor effects of intermittent conduction block in myasthenia gravis and Guillain-Barré syndrome. An oculographic study with computer simulations.
Five abnormal oculographic patterns were identified in eight patients with either myasthenia gravis or Guillain-Barré syndrome (GBS). These could be differentiated into three intrasaccadic and two postsaccadic abnormalities. From our studies of computer simulations, and considering the established pathophysiology of myasthenia gravis and GBS, we believe that our oculographic findings were a consequence of defects in peripheral neural and neuromuscular conduction, together with a simple adaptive increase in duration of the saccadic burst of central innervation. We conclude that the eye movement abnormalities we observed are explained by intermittent block of peripheral conduction, and suggest that any disease causing intermittent blockage of neural signals to extraocular muscles will produce similar abnormalities of eye movement.


[Passive hemagglutination reaction in differentiating foot-and-mouth disease viruses].
Experiments were carried out with the use of the passive hamagglutination reaction in the differentiation of foot-and-mouth disease viruses. The investigations made use of purified sera and specific IgG antibodies obtained through column chromatography. Conjugates were prepared with the use of bis-diazotized benzidine and glutaraldehyde. In experiments with conjugates prepared with IgG and glutaraldehyde standard and reproducible results were obtained. The use of the passive hemagglutination test has led to the successful differentiation of F. M. D. viruses of various origins. Comparative investigations with the complements-fixation test and the passive hemagglutination test have shown that the latter is more readily applicable and rapid as well as more sensitive.


The SPARC-related factor SMOC-2 promotes growth factor-induced cyclin D1 expression and DNA synthesis via integrin-linked kinase.
Secreted modular calcium-binding protein-2 (SMOC-2) is a recently-identified SPARC-related protein of unknown function. In mRNA profiling experiments we, found that SMOC-2 expression was elevated in quiescent (G0) mouse fibroblasts and repressed after mitogenic stimulation with serum. The G0-specific expression of SMOC-2 was similar to that of platelet-derived growth factor-beta receptor (PDGFbetaR), a major mitogenic receptor. Therefore, we tested a possible role for SMOC-2 in growth factor-induced cell cycle progression. SMOC-2 overexpression augmented DNA synthesis induced by serum and fibroblast mitogens (including PDGF-BB and basic fibroblast growth factor). Conversely, SMOC-2 ablation by using small interfering RNA attenuated DNA synthesis in response to PDGF-BB and other growth factors. Mitogen-induced expression of cyclin D1 was attenuated in SMOC-2-ablated cells, and cyclin D1-overexpressing cells were resistant to inhibition of mitogenesis after SMOC-2 ablation. Therefore, cyclin D1 is limiting for G1 progression in SMOC-2-deficient cells. SMOC-2 ablation did not inhibit PDGF-induced PDGFbetaR autophosphorylation or PDGF-BB-dependent activation of mitogen-activated protein kinase and Akt kinases, suggesting that SMOC-2 is dispensable for growth factor receptor activation. However, integrin-linked kinase (ILK) activity was reduced in SMOC-2-ablated cells. Ectopic expression of hyperactive ILK corrected the defective mitogenic response of SMOC-2-deficient cells. Therefore, SMOC-2 contributes to cell cycle progression by maintaining ILK activity during G1. These results identify a novel role for SMOC-2 in cell cycle control.


Pneumatic microvalve-based hydrodynamic sample injection for high-throughput, quantitative zone electrophoresis in capillaries.
A hybrid microchip/capillary electrophoresis (CE) system was developed to allow unbiased and lossless sample loading and high-throughput repeated injections. This new hybrid CE system consists of a poly(dimethylsiloxane) (PDMS) microchip sample injector featuring a pneumatic microvalve that separates a sample introduction channel from a short sample loading channel, and a fused-silica capillary separation column that connects seamlessly to the sample loading channel. The sample introduction channel is pressurized such that when the pneumatic microvalve opens briefly, a variable-volume sample plug is introduced into the loading channel. A high voltage for CE separation is continuously applied across the loading channel and the fused-silica capillary separation column. Analytes are rapidly separated in the fused-silica capillary, and following separation, high-sensitivity MS detection is accomplished via a sheathless CE/ESI-MS interface. The performance evaluation of the complete CE/ESI-MS platform demonstrated that reproducible sample injection with well controlled sample plug volumes could be achieved by using the PDMS microchip injector. The absence of band broadening from microchip to capillary indicated a minimum dead volume at the junction. The capabilities of the new CE/ESI-MS platform in performing high-throughput and quantitative sample analyses were demonstrated by the repeated sample injection without interrupting an ongoing separation and a linear dependence of the total analyte ion abundance on the sample plug volume using a mixture of peptide standards. The separation efficiency of the new platform was also evaluated systematically at different sample injection times, flow rates, and CE separation voltages.


Learned Spatial Schemas and Prospective Hippocampal Activity Support Navigation After One-Shot Learning.
Prior knowledge structures (or schemas) confer multiple behavioral benefits. First, when we encounter information that fits with prior knowledge structures, this information is generally better learned and remembered. Second, prior knowledge can support prospective planning. In humans, memory enhancements related to prior knowledge have been suggested to be supported, in part, by computations in prefrontal and medial temporal lobe (MTL) cortex. Moreover, animal studies further implicate a role for the hippocampus in schema-based facilitation and in the emergence of prospective planning signals following new learning. To date, convergence across the schema-enhanced learning and memory literature may be constrained by the predominant use of hippocampally dependent spatial navigation paradigms in rodents, and non-spatial list-based learning paradigms in humans. Here, we targeted this missing link by examining the effects of prior knowledge on human navigational learning in a hippocampally dependent virtual navigation paradigm that closely relates to foundational studies in rodents. Outside the scanner, participants overlearned Old Paired Associates (OPA- item-location associations) in multiple spatial environments, and they subsequently learned New Paired Associates (NPA-new item-location associations) in the environments while undergoing fMRI. We hypothesized that greater OPA knowledge precision would positively affect NPA learning, and that the hippocampus would be instrumental in translating this new learning into prospective planning of navigational paths to NPA locations. Behavioral results revealed that OPA knowledge predicted one-shot learning of NPA locations, and neural results indicated that one-shot learning was predicted by the rapid emergence of performance-predictive prospective planning signals in hippocampus. Prospective memory relationships were not significant in parahippocampal cortex and were marginally dissociable from the primary hippocampal effect. Collectively, these results extend understanding of how schemas impact learning and performance, showing that the precision of prior spatial knowledge is important for future learning in humans, and that the hippocampus is involved in translating this knowledge into new goal-directed behaviors.


Biogeophysical Impacts of Land-Use Change on Climate Extremes in Low-Emission Scenarios: Results From HAPPI-Land.
The impacts of land use have been shown to have considerable influence on regional climate. With the recent international commitment to limit global warming to well below 2°C, emission reductions need to be ambitious and could involve major land-use change (LUC). Land-based mitigation efforts to curb emissions growth include increasing terrestrial carbon sequestration through reforestation, or the adoption of bioenergy crops. These activities influence local climate through biogeophysical feedbacks, however, it is uncertain how important they are for a 1.5° climate target. This was the motivation for HAPPI-Land: the half a degree additional warming, prognosis, and projected impacts-land-use scenario experiment. Using four Earth system models, we present the first multimodel results from HAPPI-Land and demonstrate the critical role of land use for understanding the characteristics of regional climate extremes in low-emission scenarios. In particular, our results show that changes in temperature extremes due to LUC are comparable in magnitude to changes arising from half a degree of global warming. We also demonstrate that LUC contributes to more than 20% of the change in temperature extremes for large land areas concentrated over the Northern Hemisphere. However, we also identify sources of uncertainty that influence the multimodel consensus of our results including how LUC is implemented and the corresponding biogeophysical feedbacks that perturb climate. Therefore, our results highlight the urgent need to resolve the challenges in implementing LUC across models to quantify the impacts and consider how LUC contributes to regional changes in extremes associated with sustainable development pathways.


Associations between mortality, asthma, and health-related quality of life in an elderly cohort of Swedes.
Asthma is a common chronic health condition among the elderly and an important cause of morbidity and mortality. Some studies show that subjective assessments of health-related quality of life (HRQL) are important predictors of mortality and survival. The primary aim of this study was to investigate whether low HRQL was a predictor of mortality in elderly subjects and whether such an association differed between subjects with and without asthma. In 1990, a cohort in middle Sweden was investigated using a respiratory questionnaire. To assess HRQL, the generic instrument Gothenburg Quality of Life (GQL) was used. The participants were also investigated by spirometry and allergy testing. The present study was limited to the subjects in the oldest age group, aged 60-69 years in 1990, and included 222 subjects with clinically verified asthma, 148 subjects with respiratory symptoms but no asthma or other lung diseases, and 102 subjects with no respiratory symptoms. Mortality in the cohort was followed during 1990-2008. Altogether, 166 of the 472 subjects in the original cohort had died during the follow-up period of 1990-2008. Mortality was significantly higher in men, in older subjects, in smokers, and subjects with a low forced expiratory volume in one second (FEV(1)). There was, however, no difference in mortality between the asthmatic and the nonasthmatic groups. A higher symptoms score for GQL was significantly related to increased mortality. No association between HRQL and mortality was found when limiting the analysis to the asthmatic group, although the asthmatics had a lower symptom score for GQL compared to the other groups. A higher symptom score in the GQL instrument was significantly related to increased mortality, but this association was not found when analyzing the asthmatic group alone. The negative prognostic implications of a low HRQL in the whole group and the fact that the asthmatic group had a lower HRQL than the other group supports the use of HRQL instruments in clinical health assessments.


Cost-utility analysis in schizophrenia.
Estimation of quality of life is important to the study of the pharmacoeconomics of schizophrenia. The subject has gained popularity among policymakers, clinicians, and patients and their families, since the advent of new antipsychotic medications that are more expensive than older drugs yet have been shown to cause fewer side effects. Quantifying quality of life has been difficult, since studies often inconsistently define the concept or use rating scales that are inappropriate for the patient population. Utility analysis is a procedure that calculates subjects' preferences regarding living with various health states, given such options as trading more years of life at a lowered health state for dying sooner but having a strong health state during the last years of life. The feasibility of performing utility analysis among patients with schizophrenia was recently examined in a study carried out by the authors. This article reflects initial observations from that study of utility analysis and includes a discussion of problems still facing the study of quality of life and utility analysis.


Absolute-Structure Determination: Past, Present and Future.
Single-crystal X-ray crystallography is the major analytical technique in use today for absolute-configuration determination. The origins of absolute-structure determination, starting from Friedel's 1913 proof that the intensities of the opposites hkl and hkl are identical, are traced. The important structural principles derived from the study of chiral, but pseudo-mirror symmetric, methyprylon are described. For the present time, the use of the average and difference intensities of the opposites hkl and hkl are stressed. This leads to the use of Friedif, of 2 AD and selected D plots, of Rmerge and the D-Patterson. The best techniques for absolute-structure determination in the future are described. Some advice to the scientific community concludes the paper.


Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts.
Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with 177lutetium (177Lu)-PSMA-617 represented a pivotal step forward and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include 177Lu, 131iodide (131I), and 67copper (67Cu). Targeted alpha emitters potentially include 225actinium (225Ac), 227thorium (227Th), and 212lead (212Pb). Phase III trials are underway with both 177Lu-PSMA-617 and 177Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with 225Ac-J591 but additional data are need to launch a phase III. Data are promising with 225Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.


Effect of bile and bile acids on binding of intrinsic factor to cobalamin and intrinsic factor-cobalamin complex to ileal receptor.
Human bile or commercially available bile acids bind [57Co]cobalamin (Cbl) due to the presence of "R"-type binders, which are normally present in the former and present as a contaminant in the latter. The competition of these R proteins for the binding of Cbl by intrinsic factor (IF) could explain the in vivo inhibition attributed previously to the bile acids themselves. R protein seems to be involved in the inhibition of Cbl binding because protease digestion of either bile or bile acid abolishes the Cbl binding ability. Moreover, antibody to R protein abolishes the inhibition. Bile or bile acids do not have a direct effect on either purified IF or the IF-Cbl receptor molecule, even though bile acids increase the attachment of IF-[57Co]Cbl to ileal brush-border membranes. These data demonstrate two steps where components of bile could affect Cbl absorption: the binding of Cbl to IF and of IF-Cbl to its ileal receptor. It is not clear whether these in vitro phenomena are important for the normal absorption of Cbl in vivo.


Edible Insects in Africa in Terms of Food, Wildlife Resource, and Pest Management Legislation.
: Entomophagy is an ancient and actually African tradition that has been receiving renewed attention since edible insects have been identified as one of the solutions to improve global nutrition. As any other foodstuff, insects should be regulated by the government to ensure product quality and consumer safety. The goal of the present paper was to assess the current legal status of edible insects in Africa. For that, corresponding authorities were contacted along with an extensive online search, relying mostly on the FAOLEX database. Except for Botswana, insects are not mentioned in national regulations, although the definitions for "foodstuff" allow their inclusion, i.e., general food law can also apply to insects. Contacted authorities tolerated entomophagy, even though no legal base existed. However, insects typically appear in laws pertaining the use of natural resources, making a permit necessary (in most cases). Pest management regulation can also refer to edible species, e.g., locusts or weevils. Farming is an option that should be assessed carefully. All this creates a complex, nation-specific situation regarding which insect may be used legally to what purpose. Recommendations for elements in future insect-related regulations from the food hygiene point of view are provided.


Mycobacteria and subgroups of patients in Crohn's disease.
Some recent studies have proposed a subclassification of Crohn's Disease (CD) on the basis of the pathological picture. In fact CD is a heterogeneous disease, and it is probable that the clinical and pathological disorders we now consider as CD may in the near future be divided into several conditions, probably with different causes as well, including environmental factors. Clinical and pathological similarities to mycobacterial disease, along with recent isolation of mycobacteria from tissues taken from patients with CD, and the recognition of atypical mycobacteria as causative agents of an enteritis pathologically similar to CD, all go to strengthen the hypothesis that these organisms are one of the above environmental factors. Researchers should therefore seek to identify and characterize this subgroup of CD patients who may have mycobacterial disease and to perform trials of antimycobacterial therapy. Analysis of the literature gives some suggestions for identifying this subgroup of patients: i) isolation of atypical mycobacteria from the tissues; ii) presence of high specific antibody levels and increase of same after antimycobacterial therapy; iii) presence of granulomas, and iv) strong suspicion of an environmental factor.


Design of a Tool Integrating Force Sensing With Automated Insertion in Cochlear Implantation.
The quality of hearing restored to a deaf patient by a cochlear implant in hearing preservation cochlear implant surgery (and possibly also in routine cochlear implant surgery) is believed to depend on preserving delicate cochlear membranes while accurately inserting an electrode array deep into the spiral cochlea. Membrane rupture forces, and possibly, other indicators of suboptimal placement, are below the threshold detectable by human hands, motivating a force sensing insertion tool. Furthermore, recent studies have shown significant variability in manual insertion forces and velocities that may explain some instances of imperfect placement. Toward addressing this, an automated insertion tool was recently developed by Hussong et al. By following the same insertion tool concept, in this paper, we present mechanical enhancements that improve the surgeon's interface with the device and make it smaller and lighter. We also present electomechanical design of new components enabling integrated force sensing. The tool is designed to be sufficiently compact and light that it can be mounted to a microstereotactic frame for accurate image-guided preinsertion positioning. The new integrated force sensing system is capable of resolving forces as small as 0.005 N, and we provide experimental illustration of using forces to detect errors in electrode insertion.


Sulfur and oxygen isotope fractionation during benzene, toluene, ethyl benzene, and xylene degradation by sulfate-reducing bacteria.
We examined the oxygen and sulfur isotope fractionation of sulfate during anaerobic degradation of toluene by sulfate-reducing bacteria in culture experiments with Desulfobacula toluolica as a type strain and with an enrichment culture Zz5-7 obtained from a benzene, toluene, ethylbenzene, and xylene (BTEX)-contaminated aquifer. Sulfur isotope fractionation can show considerable variation upon sulfate reduction and may react extremely sensitively to changes in environmental conditions. In contrast, oxygen isotope fractionation seems to be less sensitive to environmental changes. Our results clearly indicate that oxygen isotope fractionation is dominated by isotope exchange with ambient water. To verify our experimental results and to test the applicability of oxygen and sulfur isotope investigations under realistic field conditions, we evaluated isotope data from two BTEX-contaminated aquifers presented in the recent literature. On a field scale, bacterial sulfate reduction may be superimposed by processes such as dispersion, adsorption, reoxidation, or mixing. The dual isotope approach enables the identification of such sulfur transformation processes. This identification is vital for a general qualitative evaluation of the natural attenuation potential of the contaminated aquifer.