[Human pharmacokinetics of molsidomine].
Molsidomine is well absorbed by the gastro-intestinal tract and is taken up by the liver during the first passage. Its bioavailability is 60 per cent. Digestive or sublingual absorption is rapid: maximal plasma concentrations are obtained 0.5 to 1.0 hours after administration. Molsidomine is minimally bound by plasma proteins and is distributed in a volume of 1 litre/kg. The excretion is essentially extrarenal: less than 2 per cent of the administered dose is excreted in the form of unchanged molsidomine. Molsidomine is metabolized in the liver to two pharmacologically active metabolites which spontaneously and rapidly breakdown into inactive metabolites which are excreted by the kidneys. The plasma half-life of molsidomine is 1 to 2 hours: it is not modified in patients with renal failure, but it is prolonged in patients with hepatic failure. The kinetics are linear and independent of the route of administration and the dose. There is a correlation between the plasma concentration and the pharmacological effect: the minimal effective concentration is about 5 ng/ml. At the usual dose of 2 mg three times a day, there is no accumulation of the drug.


Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses.
Medication used for acute aggression in psychiatry must have rapid onset of effect, low frequency of administration and low levels of adverse effects. Zuclopenthixol acetate is said to have these properties. To estimate the clinical effects of zuclopenthixol acetate for the management of acute aggression or violence thought to be due to serious mental illnesses, in comparison to other drugs used to treat similar conditions. We supplemented past searches of Current Controlled Trials (10/2000), the Cochrane Library (1997) and MEDLINE (1966-1997) and appeals for unpublished data with an update search of the Cochrane Schizophrenia Group's Register of trials (September 2003). All randomised clinical trials involving people thought to have serious mental illnesses comparing zuclopenthixol acetate with other drugs. Data were extracted independently by two reviewers and cross-checked. We calculated fixed effects relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. Where possible, the number needed to treat/harm statistic (NNT/H) was calculated. We analyzed by intention-to-treat. Mean differences were used for continuous variables. We found no data for the primary outcome, tranquilisation. Compared with haloperidol, zuclopenthixol acetate was no more sedating at two hours (n=40, 1 RCT, RR 0.60 CI 0.27 to 1.34). People given zuclopenthixol acetate were not at reduced risk of being given supplementary antipsychotics (n=134, 3 RCTs, RR 1.49 CI 0.97 to 2.30) although additional use of benzodiazepines was less (n=50, 1 RCT, RR 0.03 CI 0.00 to 0.47, NNT 2 CI 2 to 4). People given zuclopenthixol acetate had fewer injections over seven days compared with those allocated to haloperidol IM (n=70, 1 RCT, RR 0.39 CI 0.18 to 0.84, NNT 4 CI 3 to 14). We found no data on more episodes of aggression or harm to self or others. One trial (n=148) reported no significant difference in adverse effects for people receiving zuclopenthixol acetate compared with those allocated haloperidol at one, three and six days (RR 0.74 CI 0.43 to 1.27). Compared with haloperidol or clotiapine, people allocated zuclopenthixol did not seem to be at more risk of a range of movement disorders (<20%). Three studies found no difference in the proportion of people getting blurred vision/ dry mouth (n=192, 2 RCTs, RR at 24 hours 0.90 CI 0.48 to 1.70). Similarly dizziness was equally infrequent for those allocated zuclopenthixol acetate compared with haloperidol (n=192, 2 RCTs, RR at 24 hours 1.15 CI 0.46 to 2.88). There was no difference between treatments for leaving the study before completion (n=522, RR 0.85 CI 0.31 to 2.31). Recommendations on the use of zuclopenthixol acetate for the management of psychiatric emergencies in preference to 'standard' treatment have to be viewed with caution. Most trials present important methodological flaws and findings are poorly reported. This review did not find any suggestion that zuclopenthixol acetate is more or less effective in controlling aggressive acute psychosis, or in preventing adverse effects than intramuscular haloperidol, and neither seemed to have a rapid onset of action. Well-conducted pragmatic randomised controlled trials are needed.


Double-stranded RNA binding of influenza B virus nonstructural NS1 protein inhibits protein kinase R but is not essential to antagonize production of alpha/beta interferon.
Expression of alpha/beta interferon (IFN-alpha/beta) in virus-infected vertebrate cells is a key event in the establishment of a sustained antiviral response, which is triggered by double-stranded RNA (dsRNA) produced during viral replication. These antiviral cytokines initiate the expression of cellular proteins with activities that limit the replication and spread of the invading viruses. Within this response, the dsRNA-dependent protein kinase R (PKR) that is expressed at constitutive levels and upregulated by IFN-alpha/beta acts as an important antiviral effector that can block the cellular translational machinery. We previously demonstrated that efficient replication of influenza B virus depends on the viral dsRNA-binding NS1 protein that inhibits the transcriptional activation of IFN-alpha/beta genes. Here we tested the postulate that the viral NS1 protein counteracts antiviral responses through sequestering intracellular dsRNA by analyzing a collection of recombinant influenza B viruses. As expected, viruses expressing dsRNA-binding-defective NS1 proteins were strongly attenuated for replication in IFN-competent hosts. Interestingly, these virus mutants failed to prevent activation of PKR but could effectively limit IFN induction. Conversely, a mutant virus expressing the N-terminal dsRNA-binding domain of NS1 prevented PKR activation, but not IFN induction, suggesting an important role for the NS1 C-terminal part in silencing the activation route of IFN-alpha/beta genes. Thus, our findings indicate an unexpected mechanistic dichotomy of the influenza B virus NS1 protein in the suppression of antiviral responses, which involves at least one activity that is largely separable from dsRNA binding.


It might be premature to reject the assumption of a power curve relationship between VAS and SG data: three comments on Stevens, McCabe and Brazier's 'Mapping between VAS and SG data; results from the UK HUI Index 2 valuation survey'.
In a recent paper in Health Economics, Stevens, McCabe and Brazier (Health Econ. 2006; 15: 527-533.) found that the cubic relationship between Visual Analog Scale (VAS) values and standard gamble (SG) utilities was superior to other functional forms in terms of explanatory power and predictive ability. Consequently, they question the reliance on the assumption of a power curve relationship, which was established, theoretically and empirically, in earlier works. This note argues that: (1) SMB's conclusions are incorrect. The estimated cubic function overfits the four data points, and is questionable with respect to the implied attitude toward relative risk. (2) The evaluation of the functional forms in terms of the individual predictions' mean absolute error is misleading and (3) correcting for heteroscedasticity improves the precision of the estimates and of the predictions.


Medical leadership in the NHS during the COVID-19 pandemic.
Amid the global COVID-19 pandemic, adaptation of healthcare systems, with strong medical leadership, has been integral to coping with the ever-changing situation. This article is based on the personal experiences of doctors in the NHS and insights into the frontline response to this situation. It reflects on leadership dilemmas and strategies implemented to overcome them, with a focus on systems thinking and adaptive leadership.


Elevated inorganic carbon and salinity enhances photosynthesis and ATP synthesis in picoalga Picocystis salinarum as revealed by label free quantitative proteomics.
Saline soda lakes are of immense ecological value as they niche some of the most exclusive haloalkaliphilic communities dominated by bacterial and archaeal domains, with few eukaryotic algal representatives. A handful reports describe Picocystis as a key primary producer with great production rates in extremely saline alkaline habitats. An extremely haloalkaliphilic picoalgal strain, Picocystis salinarum SLJS6 isolated from hypersaline soda lake Sambhar, Rajasthan, India, grew robustly in an enriched soda lake medium containing mainly Na2CO3, 50 g/l; NaHCO3, 50 g/l, NaCl, 50 g/l (salinity ≈150‰) at pH 10. To elucidate the molecular basis of such adaptation to high inorganic carbon and NaCl concentrations, a high-throughput label-free quantitation based quantitative proteomics approach was applied. Out of the total 383 proteins identified in treated samples, 225 were differentially abundant proteins (DAPs), of which 150 were statistically significant (p < 0.05) including 70 upregulated and 64 downregulated proteins after 3 days of growth in highly saline-alkaline medium. Most DAPs were involved in photosynthesis, oxidative phosphorylation, glucose metabolism and ribosomal structural components envisaging that photosynthesis and ATP synthesis were central to the salinity-alkalinity response. Key components of photosynthetic machinery like photosystem reaction centres, adenosine triphosphate (ATP) synthase ATP, Rubisco, Fructose-1,6-bisphosphatase, Fructose-bisphosphate aldolase were highly upregulated. Enzymes peptidylprolyl isomerases (PPIase), important for correct protein folding showed remarkable marked-up regulation along with other chaperon proteins indicating their role in osmotic adaptation. Enhanced photosynthetic activity exhibited by P. salinarum in highly saline-alkaline condition is noteworthy as photosynthesis is suppressed under hyperosmotic conditions in most photosynthetic organisms. The study provided the first insights into the proteome of extremophilic alga P. salinarum exhibiting extraordinary osmotic adaptation and proliferation in polyextreme conditions prevailing in saline sodic ecosystems, potentially unraveling the basis of resilience in this not so known organism and paves the way for a promising future candidate for biotechnological applications and model organism for deciphering the molecular mechanisms of osmotic adaptation. The mass spectrometry proteomics data is available at the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD037170.


Biomedical real-time monitoring in restricted and safety-critical environments.
Biomedical signal monitoring can counteract the risk of human operator error due to inattention or fatigue in safetycritical and restrictive environments, such as in aviation, space, automobile and heavy industrial machinery operation. Real-time biomedical data acquisition is changing through advances in microelectronics fabrication, bio-MEMS and power micro-generators. Such data acquisition and processing systems are becoming increasingly miniaturised, flexible and pervasive, while data is being collected from inside the human body as well as around it. In this paper we review two related research projects exploiting this technological convergence, discuss its implications and suggest future innovation prospects through further similar cross-disciplinary synergies.


[Expression of human Sel-1-like gene and its significance in esophageal cancer].
To study the expression of SEL1L (human Sel-1-like gene) mRNA and protein and its significance in esophageal cancer. Immunohistochemical staining (S-P method) for SEL1L protein was performed in 90 samples of esophageal squamous cell carcinoma, 35 samples of normal esophageal mucosa 5 cm away from the tumor, 60 samples of esophageal mucosa adjacent to the tumor and 20 samples of esophageal squamous dysplasia. In situ hybridization for SEL1L mRNA was also carried out in the esophageal carcinoma cases and normal esophageal mucosa distant from and adjacent to the tumor. The positive rate of SEL1L mRNA was higher in esophageal carcinoma (80.0%, 72/90), as compared with that in normal esophageal mucosa distant from (14.3%, 5/35) and adjacent to (16.7%, 10/60) the tumor (P < 0.01). The positive rate of SEL1L mRNA in tumors with lymph node metastasis (92.7%, 38/41) was higher than that in tumors without lymph node metastasis (69.4%, 34/49) (P < 0.01). On the other hand, the expression rate of SEL1L protein was higher in esophageal carcinoma (87.8%, 79/90) and esophageal dysplasia (90.0%, 18/20), as compared with that in normal esophageal mucosa distant from (14.3%, 5/35) and adjacent to (13.3%, 8/60) the tumor (P < 0.01). The expression of SEL1L protein in esophageal cancer however did not correlate with age and sex of the patient, tumor location, tumor size, degree of differentiation, depth of tumor invasion, lymph node metastasis and tumor clinical stage (P > 0.05). A positive correlation was found between the expression of SEL1L mRNA and SEL1L protein (r = 0.492, P < 0.01). L1L protein expression is regulated at the transcriptional level. The high SEL1L protein expression is mainly the result of increased transcription. Overexpression of SEL1L protein is likely an early event during the pathogenesis of esophageal squamous cell carcinoma. SEL1L protein may serve as an important biomarker in identifying patients with higher risk of developing esophageal cancer.


A randomized trial of OKT3-based versus cyclosporine-based immunoprophylaxis after liver transplantation. Long-term results of a European and Australian multicenter study.
A multicenter randomized trial was performed to compare two immunosuppressive protocols after first ABO-compatible liver transplantation. Forty six patients were randomized to a 14-day treatment with Orthoclone (OKT3) in association with steroids and azathioprine, cyclosporine being progressively introduced on day 11 posttransplant. Fifty patients were randomized to a standard protocol of cyclosporine with steroids and azathioprine. Minimum follow-up was 1 year and graft and patient survivals were updated for the purpose of the study. The cumulative 1-year incidence of acute rejection tended to be greater in the cyclosporine group (75%) than in the OKT3 group (67%), especially when patients who did not receive full-course treatment with OKT3 were excluded (59%). Renal function was better preserved during the first two postoperative weeks in the OKT3 group than in the control group but plasma creatinine levels were comparable in both groups thereafter. The incidence of severe infections was lower in the OKT3 group (13.6%) than in the cyclosporine group (32%). The 4-year incidences of patient and graft survival in the OKT3 group (69% and 61%, respectively) were not different from those in the cyclosporine group (62% versus 54%, respectively). Thus this prospective trial shows that OKT3 immunoprophylaxis is a safe alternative to cyclosporine immunoprophylaxis in unselected recipients of a first liver graft.


Differential efflux of mitochondrial endonuclease G by hNoxa and tBid.
The Bcl-2 family of proteins regulates mitochondrial functions during cell death by modulating the efflux of death-promoting proteins such as cytochrome c and endonuclease G. Upon the binding of death ligands to their receptors, caspase-8 cleaves Bid, a BH3-only protein, into tBid that causes the mitochondrial damages resulting in the release of cytochrome c and endonuclease G. Also, another BH3-only protein, hNoxa, has been shown to induce the efflux of cytochrome c from the mitochondria. Whether the efflux proteins from the mitochondria in response to tBid or hNoxa are the same or different, however, has not been addressed. We have demonstrated that endonuclease G activities are not detectable among the proteins released from isolated mitochondria by hNoxa but are detectable in that by tBid. These results suggest that the efflux of proteins from the mitochondria are differentially modulated by tBid and hNoxa.


PATTERN OF ANTIHYPERTENSIVE THERAPY AMONG DIABETIC HYPERTEN- SIVE PATIENTS IN ZEWDITU MEMORIAL HOSPITAL, ADDIS ABABA.
Diabetes mellitus is becoming a common chronic disease in both developed and developing nations and is associated with significant cardiovascular disease morbidity and mortality. The presence of hypertension in patients with diabetes mellitus doubles the risk of cardiovascular disease including coronary heart disease, congestive heart failure, ischemic and hemorrhagic stroke, renalfailure and peripheral arterial disease. The aim of this study was to assess the pattern of antihypertensive drug therapy among diabetic hypertensive patients in Zewditu Memorial Hospital Diabetic Clinic in Addis Ababa. This is a hospital based retrospective review of medical records of 382 diabetic-hypertensive patients who visited the Zewditu Memorial Hospital Diabetic Clinic in the period between August 2014 and January 2015. The most frequently prescribed antihypertensive drug classes were angiotensin converting enzyme inhibitor in 321 (84%) followed by calcium channel blocker in 229 (60%) and beta blocker in 145 (38%) patients. Enalapril, nifedipine, atenolol, losartan and hydrochlorthiazide were the only angiotensin converting enzyme inhibitor, calcium channel blocker, beta blocker, angiotensin receptor blocker and diuretic prescribed, respectively. Enalapril was used as a monotherapy in 73 (19%) and nifedipine in 26(7%), patients. The recommended target systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg was achieved in only 57 (15%) patients while the remaining 325 (85%) did not attain the target blood pressure. Renal function was assessed in 351(92%) patients, of whom 23 (6%) had renal impairment with an estimated glomerular filtrate rate < 60 ml/min. The pattern of antihypertensive drug therapy in our patients was consistent with the current treatment guidelines. However, the majority of diabetic-hypertensive patients did not reach target blood pressure.


Effect of inorganic additives on solutions of nonionic surfactants VI: Further cloud point relations.
Disperse dosage forms stabilized with nonionic surfactants frequently contain electrolytes as active ingredients or adjuvants. Salting out of the surfactants by these electrolytes may cause breakdown of the dosage forms. The cloud point of an aqueous solution of octoxynol 9 was used to measure the salt effects. Electrolytes which salt octoxynol 9 out lower its cloud point, while salting-in electrolytes raise it. The observed cloud point effects are discussed according to the mechanisms involved. Salting out by dehydration in competition with octoxynol 9 for the available water was observed with sulfate and phosphate anions, sodium, potassium, and ammonium tribasications, and the nonelectrolyte sorbitol. The extensive self-association of water by hydrogen bonds at and below room temperature weakens its solvent power. Ions which reduce this self-association, breaking the structure of water, increased the cloud point of octoxynol 9. Among them were the iodide, thiocyanate, and nitroprusside anions. Ions which tighten the structure of water and enhance its self-association salted the surfactant out, lowering its cloud point. Among these were the fluoride and hydroxide anions. Complex formation between the ether linkages of octoxynol 9 and the following cations increased its cloud point: hydrogen (from strong acids), silver, magnesium, and zinc. Including published data, the only cations which do not form complexes with polyoxyethylated surfactants (and are, therefore, unable to salt them in) were the alkali metal ions sodium, potassium, and cesium and the ammonium ion.(ABSTRACT TRUNCATED AT 250 WORDS)


Painless type A aortic dissection.
Aortic dissection is an uncommon diagnosis that typically presents with acute onset of severe pain. It rarely presents with minimal to no symptoms, which carries a higher mortality risk given the delay in diagnosis. An adequate interpretation of risk factors, clinical findings and auxiliary tests constitutes a greater value for clinicians to detect this life-threatening condition. This report describes a case of type A aortic dissection in an asymptomatic patient presenting with an abnormal electrocardiogram (ECG).


Are Adult Crambid Snout Moths (Crambinae) and Larval Stages of Lepidoptera Suitable Tools for an Environmental Monitoring of Transgenic Crops? - Implications of a Field Test.
Butterflies and moths (Lepidoptera) have been suggested for the environmental monitoring of genetically modified (GM) crops due to their suitability as ecological indicators, and because of the possible adverse impact of the cultivation of current transgenic crops. The German Association of Engineers (VDI) has developed guidelines for the standardized monitoring of Lepidoptera describing the use of light traps for adult moths, transect counts for adult butterflies, and visual search for larvae. The guidelines suggest recording adults of Crambid Snout Moths during transect counts in addition to butterflies, and present detailed protocols for the visual search of larvae. In a field survey in three regions of Germany, we tested the practicability and effort-benefit ratio of the latter two VDI approaches. Crambid Snout Moths turned out to be suitable and practical indicators, which can easily be recorded during transect counts. They were present in 57% of the studied field margins, contributing a substantial part to the overall Lepidoptera count, thus providing valuable additional information to the monitoring results. Visual search of larvae generated results in an adequate effort-benefit ratio when searching for lepidopteran larvae of common species feeding on nettles. Visual search for larvae living on host plants other than nettles was time-consuming and yielded much lower numbers of recorded larvae. Beating samples of bushes and trees yielded a higher number of species and individuals. This method is especially appropriate when hedgerows are sampled, and was judged to perform intermediate concerning the relationship between invested sampling effort and obtained results for lepidopteran larvae. In conclusion, transect counts of adult Crambid Moths and recording of lepidopteran larvae feeding on nettles are feasible additional modules for an environmental monitoring of GM crops. Monitoring larvae living on host plants other than nettles and beating samples of bushes and trees can be used as a supplementary tool if necessary or desired.


The potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer.
Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents. Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors. Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC. Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.


Gc (vitamin D binding protein) subtype polymorphism and variants distribution among Saharan, Middle East, and African populations.
This article presents the results obtained by electrophoretic analysis of the group specific component polymorphism in more than 1,250 serum samples from populations living in the Sahara, the Middle East, and equatorial Africa. In addition to the alleles Gc1F and Gc1s, five variants, including one previously unknown, were found. The distribution of the alleles herein described permits speculation on exchanges and relations among the groups considered. The lowest frequencies of the gene Gc2 correspond to regions where sunlight is stronger. There is also a north-south gradient in the Gc1F gene frequency. This seems to parallel the gradient seen in skin pigmentation.


Flagellar polymorphism-dependent bacterial swimming motility in a structured environment.
Most motile bacteria use supramolecular motility machinery called bacterial flagellum, which converts the chemical energy gained from ion flux into mechanical rotation. Bacterial cells sense their external environment through a two-component regulatory system consisting of a histidine kinase and response regulator. Combining these systems allows the cells to move toward favorable environments and away from their repellents. A representative example of flagellar motility is run-and-tumble swimming in Escherichia coli, where the counter-clockwise (CCW) rotation of a flagellar bundle propels the cell forward, and the clockwise (CW) rotation undergoes cell re-orientation (tumbling) upon switching the direction of flagellar motor rotation from CCW to CW. In this mini review, we focus on several types of chemotactic behaviors that respond to changes in flagellar shape and direction of rotation. Moreover, our single-cell analysis demonstrated back-and-forth swimming motility of an original E. coli strain. We propose that polymorphic flagellar changes are required to enhance bacterial movement in a structured environment as a colony spread on an agar plate.


[New methods for the evaluation of bone quality. Bone anabolic agents and bone quality.]
Teriparatide(TPTD)products that can be used clinically in Japan include a daily subcutaneous injection form produced by genetic engineering and a weekly subcutaneous injectable TPTD acetate form produced by chemical synthesis. Published reports indicate that both forms exhibit excellent antifracture efficacy, and as the only anabolic agents that promote osteogenesis, TPTD products now occupy a prominent position. However, the two forms differ considerably, not only in frequency of administration, but also in mechanism of action. The daily form stimulates osteogenesis and accompanying resorption through more radical high bone turnover, and early in the course of treatment, intracortical porosity and apatite crystallization decrease, while immature collagen crosslinking increases. However, because daily formulations also produce an increase in cortical surface area or cortical thickness, the effects are counterbalanced, and bone strength is maintained. In contrast, the weekly form prioritizes osteogenesis, and by concurrently lowering turnover below pretreatment levels, improves trabecular bone mass and structure, and enhances strength without leading to cortical porosity and other undesirable phenomena. Abaloparatide, a PTHrP(1-34)analog that is homologous with the biologically active site of PTH drugs, is currently under development, and we eagerly anticipate further clarification of the mechanism of action of each formulation on bone.


A mechanism for both capacitative Ca(2+) entry and excitation-contraction coupled Ca(2+) release by the sarcoplasmic reticulum of skeletal muscle cells.
We have previously established that L6 skeletal muscle cell cultures display capacitative calcium entry (CCE), a phenomenon established with other cells in which Ca(2+) uptake from outside cells increases when the endoplasmic reticulum (sarcoplasmic reticulum in muscle, or SR) store is decreased. Evidence for CCE rested on the use of thapsigargin (Tg), an inhibitor of the SR CaATPase and consequently transport of Ca(2+) from cytosol to SR, and measurements of cytosolic Ca(2+). When Ca(2+) is added to Ca(2+)-free cells in the presence of Tg, the measured cytosolic Ca(2+) rises. This has been universally interpreted to mean that as SR Ca(2+) is depleted, exogenous Ca(2+) crosses the plasma membrane, but accumulates in the cytosol due to CaATPase inhibition. Our goal in the present study was to examine CCE in more detail by measuring Ca(2+) in both the SR lumen and the cytosol using established fluorescent dye techniques for both. Surprisingly, direct measurement of SR Ca(2+) in the presence of Tg showed an increase in luminal Ca(2+) concentration in response to added exogenous Ca(2+). While we were able to reproduce the conventional demonstration of CCE-an increase of Ca(2+) in the cytosol in the presence of thapsigargin-we found that this process was inhibited by the prior addition of ryanodine (Ry), which inhibits the SR Ca(2+) release channel, the ryanodine receptor (RyR). This was also unexpected if Ca(2+) enters the cytosol first. When Ca(2+) was added prior to Ry, the later was unable to exert any inhibition. This implies a competitive interaction between Ca(2+) and Ry at the RyR. In addition, we found a further paradox: we had previously found Ry to be an uncompetitive inhibitor of Ca(2+) transport through the RyR during excitation-contraction coupling. We also found here that high concentrations of Ca(2+) inhibited its own uptake, a known feature of the RyR. We confirmed that Ca(2+) enters the cells through the dihydropyridine receptor (DHPR, also known as the L-channel) by demonstrating inhibition by diltiazem. A previous suggestion to the contrary had used Mn(2+) in place of direct Ca(2+) measurements; we showed that Mn(2+) was not inhibited by diltiazem and was not capacitative, and thus not an appropriate probe of Ca(2+) flow in muscle cells. Our findings are entirely explained by a new model whereby Ca(2+) enters the SR from the extracellular space directly through a combined channel formed from the DHPR and the RyR. These are known to be in close proximity in skeletal muscle. Ca(2+) subsequently appears in the cytosol by egress through a separate, unoccupied RyR, explaining Ry inhibition. We suggest that upon excitation, the DHPR, in response to the electrical field of the plasma membrane, shifts to an erstwhile-unoccupied receptor, and Ca(2+) is released from the now open RyR to trigger contraction. We discuss how this model also resolves existing paradoxes in the literature, and its implications for other cell types.


Awareness and Interest in Uterus Transplantation over Time: Analysis of Those Seeking Surgical Correction for Uterine-Factor Infertility in the US.
This study describes the characteristics of women who contacted an active program performing uterus transplantation (UTx) in the US, expressing interest in becoming a uterus transplant recipient or a living donor. Basic demographic and self-reported clinical information was collected from women who contacted any of the three US UTx programs from 2015 to July 2022. The three centers received 5194 inquiries about becoming a UTx recipient during the study timeframe. Among those reporting a cause of infertility, almost all of the reports (4066/4331, 94%) were absence of a uterus, either congenitally (794/4066, 20%) or secondary to hysterectomy (3272/4066, 80%). The mean age was 34 years, and 49% (2545/5194) had at least one child at the time of application. The two centers using living donors received 2217 inquiries about becoming living donors. The mean age was 34 years, and 60% (1330/2217) had given birth to ≥1 child. While most of the UTx clinical trial evidence has focused on young women with congenital absence of the uterus, these results show interest from a much broader patient population in terms of age, cause of infertility, and parity. These results raise questions about whether and to what extent the indications and eligibility criteria for UTx should be expanded as the procedure transitions from the experimental phase to being offered as a clinical treatment.


Design of microfission chamber for ITER operations.
Microfission chambers (MFCs) are one of the most important diagnostics for measuring neutron source strength in ITER. Using MFCs for high-power operations (fusion power of 100 kW-1 GW) and for low-power operations (<100 kW) in combination is one way to fulfill the target measurement requirements of ITER. The MFCs for high-power operations will be installed behind blanket modules in both the upper and lower outboard regions of the vacuum vessel so as to be insensitive to changes in the position of the plasma. For low-power operations, one possible location of MFCs is inside the equatorial (EQ) port. The effect of streaming neutrons and of changes in the position of the plasma on the responses of MFCs is estimated based on a neutron Monte Carlo calculation using the MCNP Version 5 code. Results suggest that the effect of streaming neutrons should be taken into account if the MFCs for high-power operations are installed closer than 20 cm to the gap between blanket modules. It has also been found for MFCs of low-power operations that the averaged output of the MFCs installed at the top and bottom of the EQ port is sensitive to horizontal plasma shifts but not to vertical shifts. This finding suggests that corrections based on the position of the plasma center will be needed for the absolute measurement of neutron source strength.


Notes from the field: Salmonella Typhi infections associated with contaminated water--Zimbabwe, October 2011-May 2012.
On October 25, 2011, a cluster of approximately 20 suspected cases of typhoid fever in residents of Dzivaresekwa, a high-density suburb of Harare, Zimbabwe, was reported to the City of Harare City Health Department. On November 22, a team from CDC-Atlanta, CDC-Kenya/Kenya Medical Research Institute, and the South Africa Field Epidemiology and Laboratory Training Program, was invited to assist with the investigation by providing epidemiologic and microbiologic support to better describe the outbreak and to evaluate response efforts.


[Cementoma of the jaw. Clinical case].
The A.A. describe a case of cementoma come to their observation, reporting considerations resulting from an attentive analysis of the literature on the subject.


The role of Fc receptors in HIV prevention and therapy.
Over the past decade, a wealth of experimental evidence has accumulated supporting the importance of Fc receptor (FcR) ligation in antibody-mediated pathology and protection in many disease states. Here we present the diverse evidence base that has accumulated as to the importance of antibody effector functions in the setting of HIV prevention and therapy, including clinical correlates, genetic associations, viral evasion strategies, and a rapidly growing number of compelling animal model experiments. Collectively, this work identifies antibody interactions with FcR as important to both therapeutic and prophylactic strategies involving both passive and active immunity. These findings mirror those in other fields as investigators continue to work toward identifying the right antibodies and the right effectors to be present at the right sites at the right time.


Getting off on the wrong foot: the timing of a breach and the restoration of trust.
Few interpersonal relationships endure without one party violating the other's expectations. Thus, the ability to build trust and to restore cooperation after a breach can be critical for the preservation of positive relationships. Using an iterated prisoner's dilemma, this article presents two experiments that investigated the effects of the timing of a trust breach-at the start of an interaction, after 5 trials, after 10 trials, or not at all. The findings indicate that getting off on the wrong foot has devastating long-term consequences. Although later breaches seemed to limit cooperation for only a short time, they still planted a seed of distrust that surfaced in the end.


Facile synthesis of ZnS-AgInS2 solid solution nanoparticles for a color-adjustable luminophore.
Nanoparticles of ZnS-AgInS2 solid solution (ZAIS) were synthesized by the thermal decomposition of (AgIn)xZn2(1-x)(S2CN(C2H5)2)4 precursors in a hot oleylamine solution. X-ray powder diffraction analyses revealed that the resulting nanoparticle powders were not a mixture of ZnS and AgInS2 but a ZnS-AgInS2 solid solution in which the fraction of ZnS was enlarged with a decrease in the value of x, that is, an increase in the content of Zn2+ in the precursors used. The energy gap of ZAIS nanoparticles could be controlled by the composition of solid solution. Intense emission was observed at room temperature, regardless of the kind of the particles, the peak wavelength of PL being blue-shifted from 720 to 540 nm with a decrease in the value of x. The highest quantum yield of ca. 24% was obtained for nanoparticles prepared with x = 0.86, which was much higher than the quantum yields reported for I-III-VI2-based semiconductor nanoparticles, such as CuInS2 and ZnS-CuInS2 solid solution.


Substance P-saporin down-regulates substance P receptor immunoreactive sensory dorsal root ganglion neurons innervating the lumbar intervertebral discs in rats.
To examine changes in substance P receptors on dorsal root ganglion cells innervating the rat lumbar intervertebral discs using immunohistochemistry and a retrograde neurotracing method. We evaluated the effects of intradiscal administration of substance P-saporin, a toxin selective for cells expressing substance P receptors. The rat L5/6 intervertebral disc is multi-segmentally innervated from the L1-L6 dorsal root ganglions. Substance P and the neurokinin-1 receptor contribute to inflammatory pain transmission. Substance P immunoreactive-sensory nerve fibers in human intervertebral discs and immunoreactive-dorsal root ganglion neurons innervating rat intervertebral discs have been reported to be important in the transmission of discogenic low back pain. In the current study, we evaluated the effects of intradiscal administration of substance P-saporin, a toxin selective for cells expressing substance P receptor. Sixteen rats were used (control group, n = 8; substance P-saporin group, n = 8). To detect dorsal root ganglion neurons innervating the L5/6 intervertebral disc, neurotracer (fluoro-gold crystals) was placed into the intervertebral disc. Seven days after fluoro-gold application, the L5/6 intervertebral disc was exposed and injected with 175 ng of sterile substance P-saporin (substance P-saporin group, n = 8). Fourteen days after the first operation, each dorsal root ganglion was harvested, sectioned, and processed for neurokinin-1 immunohistochemistry using rabbit antibody to neurokinin-1. The numbers of fluoro-gold labeled neurons, and fluoro-gold labeled and neurokinin-1 immunoreactive neurons were counted in both groups. Neurons innervating the L5/6 intervertebral discs, retrogradely labeled with fluoro-gold, were distributed throughout dorsal root ganglions from L1 to L6 in both groups. Of fluoro-gold labeled neurons, the proportion of neurokinin-1 immunoreactive neurons was 35% in the control group. However, the proportion of neurokinin-1 immunoreactive neurons was 8% after administration of substance P-saporin into the intervertebral discs (substance P-saporin group). Substance P-saporin significantly decreased the ratio of neurokinin-1 immunoreactive neurons. Substance P-saporin decreased the ratio of neurokinin-1 immunoreactive neurons innervating the disc related to discogenic low back pain. Substance P-saporin may be a useful tool to investigate the mechanism of discogenic low back pain.


Factors contributing to the development of cerebral malaria. I. Humoral immune responses.
Humoral immune responses to malaria were studied in 100 patients with cerebral malaria of whom 53 had added complications, 108 patients with acute malaria, and 100 blood donors. The methods employed were indirect hemagglutination (IHA), indirect fluorescent antibody (IFA), enzyme-linked immunosorbent assay (ELISA), and parasite growth inhibition (PGI) tests. Patients with cerebral malaria, especially those with complications, had histories of fewer attacks of malaria in the previous 5 years than did those with acute malaria, suggesting that the cerebral malaria patients were less immune. The combined cerebral malaria group (complicated and uncomplicated) did not show defective humoral immune responses, since the initial seronegative rate and the mean initial IHA and IFA antibody titers were not significantly different from those of acute malaria patients and the mean initial ELISA titer was even higher than that of the acute malaria group. Reduced humoral responses were found only in complicated cerebral malaria patients, as their mean initial IHA titer was lower and their IHA seronegative rate was higher than those in acute malaria patients and in the uncomplicated cerebral malaria group. The combined cerebral malaria group had greater PGI activity than that of acute malaria patients, but this increased activity was entirely due to the higher results obtained in the complicated cerebral malaria group. The increased PGI activity returned to normal after recovery. An IgG preparation from seven of eight of these sera failed to exert the growth inhibition effect. Factors other than IgG were therefore responsible for the inhibition of parasite growth.


The influence of microencapsulation using Eudragit RS100 on the hydrolysis kinetics of acetylsalicylic acid.
Homogeneous Eudragit RS100 matrix microspheres containing molecularly dispersed acetylsalicylic acid (ASA) were prepared in order to investigate the effect of encapsulation on the decomposition rate of a hydrolytically susceptible drug. ASA-loaded microspheres of this non-eroding polymer matrix were analysed at predetermined time points following immersion of the microspheres in temperature controlled buffer systems at pH 1.2 or pH 12.1 at 30, 40 or 50 degrees C. The mass balance of the total amount of solutes (ASA and SA) initially located within the microsphere interior was equal to the sum of the amount of solutes remaining in the microsphere interior and the amount of solutes in the aqueous phase at any time during the course of the study. Each analysis involved the quantitation of four species; the drug and decomposition product, salicylic acid (SA), in both the microspheres phase and the external aqueous phase. A simple model system using first-order rate approximations for the concurrent Fickian diffusion and hydrolysis decomposition of the drug resulted in a multiexponential expression which adequately described the time-course profile of the drug. SA-loaded microspheres were used as a control under similar conditions to determine the magnitude of the contribution of microsphere phase hydrolysis of ASA to the overall rate of drug loss from the microspheres. Results indicated that microspheres phase hydrolysis of ASA was minimal. Even after 900 h of immersion in pH 12.1 buffer some ASA remained within the microsphere. It is postulated that the matrix incorporated drug is essentially shielded from hydrolytic attack until it is liberated into the external aqueous environment. Electrostatic association of the drug with the charged quaternary residues in the polymer along with the limiting availability of water within the microsphere may be responsible for the observed stability of ASA in aqueous swollen ASA-loaded Eudragit microspheres.


Effects of sports drinks on the maintenance of physical performance during 3 tennis matches: a randomized controlled study.
Tennis tournaments often involve playing several consecutive matches interspersed with short periods of recovery. The objective of this study was firstly to assess the impact of several successive tennis matches on the physical performance of competitive players and secondly to evaluate the potential of sports drinks to minimize the fatigue induced by repeated matches. This was a crossover, randomized controlled study. Eight male regionally-ranked tennis players participated in this study. Players underwent a series of physical tests to assess their strength, speed, power and endurance following the completion of three tennis matches each of two hours duration played over three consecutive half-days (1.5 day period for each condition). In the first condition the players consumed a sports drink before, during and after each match; in the second, they drank an identical volume of placebo water. The results obtained were compared with the third 'rest' condition in which the subjects did not play any tennis. Main outcomes measured were maximal isometric strength and fatigability of knee and elbow extensors, 20-m sprint speed, jumping height, specific repeated sprint ability test and hand grip strength. The physical test results for the lower limbs showed no significant differences between the three conditions. Conversely, on the upper limbs the EMG data showed greater fatigue of the triceps brachii in the placebo condition compared to the rest condition, while the ingestion of sports drinks attenuated this fatigue. This study has demonstrated for the first time that, when tennis players are adequately hydrated and ingest balanced meals between matches, then no large drop in physical performance is observed even during consecutive competitive matches. ClinicalTrials.gov: NCT01353872.


Vibriocidal antibody responses in North American volunteers exposed to wild-type or vaccine Vibrio cholerae O139: specificity and relevance to immunity.
The emergence of a new agent of cholera, Vibrio cholerae O139, has prompted a reevaluation of the vibriocidal antibody assay. This assay, primarily directed to lipopolysaccharide, is an important correlate of O1 immunity. V. cholerae O139 strains are encapsulated, rendering them relatively resistant to killing by serum. Recent reports suggest that there is strain-to-strain variability in the sensitivity of the vibriocidal assay to fully encapsulated O139 strains. We have assessed a modified vibriocidal assay for fully encapsulated O139 strain AI-1837 and its unencapsulated mutant 2L in sera from 53 volunteers given wild-type AI-1837 or its attenuated derivative CVD 112 and from 48 controls challenged with V. cholerae O1 or strains of the family Enterobacteriaceae. Vibriocidal responses to the AI-1837 and 2L strains were seen in 67 and 89% of volunteers, respectively, following a single exposure to the wild-type strain. However, >50% of all controls had low-level vibriocidal responses to both strains. These nonspecific responses were transient and of the immunoglobulin G isotype. No binding activity against purified O139 lipopolysaccharide (LPS) by immunoblotting was seen in control sera. In contrast, vibriocidal assay and strain 2L LPS responses by immunoblotting were detectable in 91% of tested volunteers following a single exposure to O139. The presence of vibriocidal antibody to AI-1837 or 2L was not associated with protection in rechallenge studies with O139 strain AI-1837. The vibriocidal assay with unencapsulated strain 2L may be used to detect exposure to O139 strain AI-1837 in controlled research trials. However, its lack of specificity does not make it useful for determining exposure to V. cholerae O139 in the field.


Cutting edge: TRAIL deficiency accelerates hematological malignancies.
TNF apoptosis-inducing ligand is attracting considerable interest as a potential extrinsic tumor suppressor mechanism, although previous reports have conveyed somewhat contrasting views regarding the likely importance of this pathway. In this study, we provide the first evaluation of spontaneous tumor formation over the life span of TRAIL-deficient mice. Interestingly, >25% of these mice do develop lymphoid malignancies after 500 days of life. TRAIL suppressed the initiation and development of both tumors of lymphoid and stromal origin in the context of the loss of at least one p53 allele. Specific examination of the role of TRAIL in Her2/neu oncogene-driven mammary epithelial cancer revealed no critical role for TRAIL despite the inherent TRAIL sensitivity of such mammary carcinomas. Overall, the data indicate an important function of TRAIL in controlling carcinogenesis, but suggest that further examination of this pathway in epithelial malignancies is warranted.


A tetrabromo-1,4-ethanonaphthalene and related dibromo-1,4-ethenonaphthalene.
(1RS,3RS,4RS,10SR)-2,2,3,10-Tetrabromo-1,2,3,4-tetrahydro-1,4-ethanonaphthalene, C12H10Br4, (I), is the first structure to be reported with four Br atoms bound to a 1,4-ethanonaphthalene framework and also the first which possesses three Br atoms in exo positions. Interactions between the Br atoms [three short intramolecular Br...Br distances of 3.1094 (4), 3.2669 (4) and 3.4415 (5) Å] have little effect on the C-C bond lengths but lead to significant twisting of the cage structure compared with the parent hydrocarbon, which is expected to be fully eclipsed at the two saturated C2H4 bridge positions. Chemically related (1SR,4RS)-2,3-dibromo-1,4-ethenonaphthalene, C12H8Br2, (II), obtained by double dehydrobromination of (I), represents the first structure of any halogen-substituted benzobarrelene. This cis-dibromide shows little evidence of steric congestion at the double bond [Br...Br = 3.5276 (8) Å] as a consequence of the large C-C-Br angles [average C=C-Br angle = 126.15 (10)°].


Hydrothermal synthesis in the system Ni(OH)(2)-NiSO(4): nuclear and magnetic structures and magnetic properties of Ni(3)(OH)(2)(SO(4))(2)(H(2)O)(2).
We present the synthesis, characterization by DT-TGA and IR, single crystal X-ray nuclear structure at 300 K, nuclear and magnetic structure from neutron powder diffraction on a deuterated sample at 1.4 K, and magnetic properties as a function of temperature and magnetic field of Ni(3)(OH)(2)(SO(4))(2)(H(2)O)(2). The structure is formed of chains, parallel to the c-axis, of edge-sharing Ni(1)O(6) octahedra, connected by the corners of Ni(2)O(6) octahedra to form corrugated sheets along the bc-plane. The sheets are connected to one another by the sulfate groups to form the 3D network. The magnetic properties measured by ac and dc magnetization, isothermal magnetization at 2 K, and heat capacity are characterized by a transition from a paramagnet (C = 3.954 emu K/mol and theta = -31 K) to a canted antiferromagnet at T(N) = 29 K with an estimated canting angle of 0.2-0.3 degrees. Deduced from powder neutron diffraction data, the magnetic structure is modeled by alternate pairs of Ni(1) within a chain having their moments pointing along [010] and [010], respectively. The moments of Ni(2) atoms are oppositely oriented with respect to their adjacent pairs. The resulting structure is that of a compensated arrangement of moments within one layer, comprising one ferromagnetic and three antiferromagnetic superexchange pathways between the nickel atoms.


One-step synthesis and pharmacological activity of new (N-substituted)amino-spiroalkan-dione derivatives.
The synthesis of (N-substituted)amino-spiroalkan-dione derivatives 3 is described starting from enamines 1 and carbon suboxide 2, and their inhibitory effects on blood coagulation in vivo and on platelet aggregation in vitro are determined. Some of synthesized compounds showed a strong anticoagulant activity. A comparative pharmacological study of the anticoagulant effects of the new compounds versus Warfarin suggests that their behaviour is analogous, though the action mechanism is different.


Leisure-Time and Occupational Physical Activity in Early and Late Adulthood in Relation to Later Life Physical Functioning.
Physical activity (PA) has beneficial effects on older age physical functioning, but longitudinal studies with follow-ups extending up to decades are few. We investigated the association between leisure-time PA (LTPA) and occupational PA (OPA) from early to late adulthood in relation to later life performance-based physical functioning. The study involved 1260 people aged 60 to 79 years who took part in assessments of physical functioning (Short Physical Performance Battery [SPPB] test, 10-m maximal walking test, and grip strength test). Participants' data on earlier life LTPA/OPA (age range 25 to 74 years) were received from the previous studies (average follow-up 13.4 years). Logistic, linear, and censored regression models were used to assess the associations between LTPA/OPA earlier in life and subsequent physical functioning. A high level of LTPA earlier in life was associated with a lower risk of having difficulties on the SPPB test (odds ratio [OR]: 0.37; 95% confidence interval [CI], 0.24-0.58) and especially on the chair rise test (OR: 0.42; 95% CI, 0.27-0.64) in old age. Heavy manual work predicted difficulties on SPPB (OR: 1.91; 95% CI, 1.22-2.98) and the chair rise test (OR: 1.75; 95% CI, 1.14-2.69) and poorer walking speed (β = .10, P = .005). This study highlights the importance of LTPA on later life functioning, but also indicates the inverse effects that may be caused by heavy manual work.


Defining lipid-interacting domains in the N-terminal region of apolipoprotein B.
Apolipoprotein B (apoB) is a nonexchangeable apolipoprotein that dictates the synthesis of chylomicrons and very low density lipoproteins. ApoB is the major protein in low density lipoprotein, also known as the "bad cholesterol" that is directly implicated in atherosclerosis. It has been suggested that the N-terminal domain of apoB plays a critical role in the formation of apoB-containing lipoproteins through the initial recruitment of phospholipids in the endoplasmic reticulum. However, very little is known about the mechanism of lipoprotein nucleation by apoB. Here we demonstrate that a strong phospholipid remodeling function is associated with the predicted alpha-helical and C-sheet domains in the N-terminal 17% of apoB (B17). Using dimyristoylphosphatidylcholine (DMPC) as a model lipid, these domains can convert multilamellar DMPC vesicles into discoidal-shaped particles. The nascent particles reconstituted from different apoB domains are distinctive and compositionally homogeneous. This phospholipid remodeling activity is also observed with egg phosphatidylcholine (egg PC) and is therefore not DMPC-dependent. Using kinetic analysis of the DMPC clearance assay, we show that the identified phospholipid binding sequences all map to the surface of the lipid binding pocket in the B17 model based on the homologous protein, lipovitellin. Since both B17 and microsomal triglyceride transfer protein (MTP), a critical chaperone during lipoprotein assembly, are homologous with lipovitellin, the identification of these phospholipid remodeling sequences in B17 provides important insights into the potential mechanism that initiates the assembly of apoB-containing lipoproteins.


Effects of visual illusions on grasping.
In 2 experiments, the Muller-Lyer illusion (F. C. Muller-Lyer, 1889; N = 16) and the parallel-lines illusion (W. Wundt, 1898; N = 26) clearly affected maximum preshape aperture in grasping (both ps < .001). The grasping effects were similar but not perfectly equal to the perceptual effects. Control experiments show that these differences can be attributed to problems in matching the perceptual task and the grasping task. A model is described stating the assumptions that are needed to compare the grasping effects and the perceptual effects of visual illusions. Further studies on the relationship between perception and grasping are reviewed. These studies provide no clear evidence for a dissociation between perception and grasping and therefore do not support the action versus perception hypothesis (A. D. Milner & M. A. Goodale, 1995).


Initial experience with three-dimensional heads-up display system for cataract surgery - A comparative study.
: To compare the complication rates, surgical time and learning curve using the 3-D Heads up display system in comparison with the conventional microscope for routine cataract surgery. : Consecutive consenting adults with uncomplicated cataract were offered phacoemulsification using the 3-D Heads up display system (ARTEVO 800 Carl Zeiss Meditec) or the conventional microscope (Zeiss Lumera 700) by two experienced surgeons. Surgical time, measured from start of corneal incision to removal of microscope from the surgical field and complication rates were compared between the groups. : Of the 343 eyes enrolled, 100 (29%) underwent surgery using the 3-D Heads up display system. The surgical time for 3-D Heads up display system was significantly higher in the 3-D group (8.4 ± 2.1 vs. 6.5 ± 1.8 minutes, P < 0.001). There were no group differences in surgical complications (2% in 3-D vs. 2.5% in conventional microscope, P = 0.28). Comparing across 4 quartiles within the 3-D group, the mean surgical time was slightly higher during the 1st quartile (n = 25, 9.1 ± 1.9 minutes) compared to the last quartile (n = 25, 8.2 ± 1.9 minutes) (p = 0.17). Complications in the 3-D group occurred only in the initial 50% of cases. Seven (7%) cases in the 3-D group were converted to conventional binocular microscope of which 3 each were due to difficulty in depth perception and low illumination while one was due to intraoperative pupillary constriction. : Phacoemulsification with the 3-D Heads up display system takes longer time but offers excellent visualization, ergonomics and safety compared to conventional microscopes. Experienced surgeons should be able to adapt easily after their first 50 surgeries.


Geriatric Nutrition Risk Index is an Important Predictor of Cancer-Specific Survival, but not Recurrence-Free Survival, in Patients Undergoing Surgical Resection for Non-Metastatic Renal Cell Carcinoma.
The objective of this study was to assess the prognostic value of the Geriatric Nutrition Risk Index (GNRI), a simplified, objective screening parameter of nutrition-related risk for various pathological conditions, on patients with non-metastatic renal cell carcinoma (RCC) who underwent surgical resection. This study included 432 consecutive patients with non-metastatic RCC who received complete surgical resection. The prognostic outcomes of these patients were evaluated focusing on the significance of GNRI, calculated from serum albumin and the body mass index. Of the 432 patients, 107 (24.8%) and 325 (75.2%) were classified into low (GNRI ≤ 98) and high (GNRI > 98) nutritional groups, respectively. Both recurrence-free survival and cancer-specific survival in the low nutritional group were significantly poorer compared with those in the high nutritional group. Despite the lack of independent significance as a predictor of recurrence-free survival, GNRI, in addition to microvascular invasion, appeared to be independently associated with cancer-specific survival on multivariate analysis. A low nutritional status evaluated by GNRI may have an unfavorable impact on postoperative cancer control, particularly cancer-specific survival, in non-metastatic RCC patients who received surgical resection.


Limitations in the clinical usefulness of single-dose pharmacokinetic studies of drugs and a bayesian approach for the estimation of kinetic parameters.
This review presents several clinical examples indicating that physiological changes in the body dependent and/or independent of developmental age, genetic polymorphisms, different disease states, acute and/or chronic inflammations, and physicochemical properties of drugs as well as some environmental factors, such as viral infections, may exert a significant effect on the first-time assessment of kinetic parameters of drug absorption, disposition, metabolism, and excretion after a single-dose administration in children and adults. The available pharmacokinetic data in the literature suggest that one must be cautious in interpretation and practical use of pharmacokinetic variables derived from either single-dose studies or bayesian methods, especially in a pediatric population.


Nuclear factor kappa B activation and regulation of cyclooxygenase type-2 expression in human amnion mesenchymal cells by interleukin-1beta.
Interleukin-1beta (IL-1beta) has been shown in numerous studies to increase prostaglandin (PG) output by up-regulating the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in PG synthesis. In this study, we investigated the possible role of the nuclear factor kappa B (NFkappaB) in IL-1beta signaling, leading to the expression of COX-2 in human amnion cell culture. Fetal amnion was obtained following vaginal delivery and digested with collagenase, and the subepithelial (mesenchymal) cells were isolated. Cultures were characterized with antisera to keratin (epithelial cells) and vimentin (mesenchymal cells). Confluent cells were stimulated with human recombinant IL-1beta, and activation of NFkappaB was assessed by measuring changes in the inhibitory protein IkappaB (total IkappaB and phosphorylated IkappaB) using Western blot analysis as well as by nuclear binding of NFkappaB using an electrophoretic mobility shift assay. COX-2 protein levels were determined by Western blot analysis. After 5 min of stimulation with IL-1beta, phosphorylated IkappaB began to appear, 90% of which was degraded within 15 min. This was temporally associated with decreased total IkappaB and increased nuclear NFkappaB DNA-binding activity. In the IL-1beta-treated group, COX-2 protein began to increase after 6 h; this response was time-dependent, with a significant increase until 24 h after IL-1beta stimulation. When NFkappaB translocation was blocked by using SN50 (a cell-permeable inhibitory peptide of NFkappaB translocation), the synthesis of COX-2 protein was inhibited. These results suggest that NFkappaB is involved in the IL-1beta-induced COX-2 expression in the mesenchymal cells of human amnion.


Infections and the inflammatory response in acute respiratory distress syndrome.
Systemic inflammatory response syndrome (SIRS) and infections are frequently associated with the development and progression of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). We investigated, at onset and during the progression of ARDS, the relationships among (1) clinical variables and biological markers of SIRS, (2) infections defined by strict criteria, and (3) patient outcome. Biological markers of SIRS included serial measurements of inflammatory cytokines (IC)-tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8-in plasma and BAL fluid. We prospectively studied two groups of ARDS patients: 34 patients treated conventionally (group 1) and nine patients who received glucocorticoid rescue treatment for unresolving ARDS (group 2). Individual SIRS criteria and SIRS composite score were recorded daily for all patients. Plasma IC levels were measured by enzyme-linked immunosorbent assay on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients received mechanical ventilation. Unless contraindicated, bilateral BAL was performed on day 1, weekly, and when ventilator-associated pneumonia was suspected. Patients were closely monitored for the development of nosocomial infections (NIs). ICU mortality was similar among patients with and without sepsis on admission (54% vs 40%; p < 0.45). Among patients with sepsis-induced ARDS, mortality was higher in those who subsequently developed NIs (71% vs 18%; p < 0.05). At the onset of ARDS, plasma TNF-alpha, IL-1 beta, IL-6, and IL-8 levels were significantly higher (p < 0.0001) in nonsurvivors (NS) and in those with sepsis (p < 0.0001). The NS group, contrary to survivors (S), had persistently elevated plasma IC levels over time. In 17 patients, 36 definitive NIs (17 in group 1 and 19 in group 2) were diagnosed by strict criteria. No definitive or presumed NIs caused an increase in plasma IC levels above patients' preinfection baseline. Daily SIRS components and SIRS composite scores were similar among S and NS and among patients with and without sepsis-induced ARDS, were unaffected by the development of NI, and did not correlate with plasma IC levels. Sepsis as a precipitating cause of ARDS was associated with higher plasma IC levels. However, NIs were not associated with an increase in SIRS composite scores, individual SIRS criteria, or plasma IC levels above patients' preinfection baseline. SIRS composite scores over time were similar in S and NS. SIRS criteria, including fever, were found to be nonspecific for NI. Irrespective of etiology of ARDS, plasma IC levels, but not clinical criteria, correlated with patient outcome. These findings suggest that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response and is independent of the precipitating cause of ARDS or the development of intercurrent NIs.


Translational advances in pancreatic ductal adenocarcinoma therapy.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is most frequently detected at advanced stages, limiting treatment options to systemic chemotherapy with modest clinical responses. Here, we review recent advances in targeted therapy and immunotherapy for treating subtypes of PDAC with diverse molecular alterations. We focus on the current preclinical and clinical evidence supporting the potential of these approaches and the promise of combinatorial regimens to improve the lives of patients with PDAC.


Antenatal care satisfaction in a developing country: a cross-sectional study from Nigeria.
Utilization of Antenatal Care (ANC) is very low in Nigeria. Self-reported patient satisfaction may be useful to identify provider- and facility-specific factors that can be improved to increase ANC satisfaction and utilization. Exit interview data collected from ANC users and facility assessment survey data from 534 systematically selected facilities in four northern Nigerian states were used. Associations between patient satisfaction (satisfied, not-satisfied) and patient ratings of the provider's interactions, care processes, out-of-pocket costs, and quality of facility infrastructure were studied. Of 1336 mothers, 90% were satisfied with ANC. Patient satisfaction was positively associated with responsive service (prompt, unrushed service, convenient clinic hours and privacy during consultation, AOR 2.42, 95% CI 2.05-2.87), treatment-facilitation (medical care-related provider communication and ease of receiving medicines, AOR 2.03, 95% CI 1.46-2.80), equipment availability (AOR 1.10, 95% CI 1.01-1.21), staff empathy (AOR 1.82, 95% CI 1.03-3.23), non-discriminatory treatment regardless of patient's socioeconomic status (AOR: 1.87, 95% CI 1.09-3.22), provider assurance (courtesy and patient's confidence in provider's competence, AOR 1.48, 95% CI 1.26-1.75), and number of clinical examinations received (AOR 1.28, 95% CI 1.10-1.50). ANC satisfaction was negatively impacted by out-of-pocket payment for care (vs. free care, AOR 0.44, 95% CI 0.23-0.82). ANC satisfaction in Nigeria may be enhanced by improving responsiveness to clients, clinical care quality, ensuring equipment availability, optimizing easy access to medicines, and expanding free ANC services.


[Surgical treatment of massive rebleeding after gastrectomy for bleeding gastroduodenal ulcer].
To summarize the reoperation experiences in treatment of massive rebleeding after subtotal gastrectomy for bleeding gastroduodenal ulcer. From 1980 to 2002, clinical data of 26 cases with massive rebleeding after subtotal gastrectomy for bleeding gastrorenal ulcer were analyzed retrospectively. Preoperative gastroscopy was performed in 6 cases, intraoperative gastroscopy in 11, and preoperative superselective angiography in 2 cases. Eleven cases with left ulcer or post- bulb ulcer bleeding underwent resection of the left ulcer or longitudinal incision of the duodenal descending part and direct hemostasis. Thirteen cases with anastomotic stoma bleeding underwent local suture hemostasis or resection of the stoma plus Billroth II or Roux- en- Y gastrojejunostomy. Two cases with gastric bleeding received reexcision of the stomach remnant. Twenty- four cases (92.3% ) were cured and 2 cases (7.7% ) died of gastric bleeding. Preoperative superselective angiography and intraoperative gastroscopy are beneficial to clarify the bleeding position and causes for massive rebleeding after gastrectomy. It is very important to select proper operative method to prevent postoperative rebleeding.


Vitamin D and Vitamin D from Ultraviolet-Irradiated Mushrooms (Review).
Vitamin D may have an important role in many aspects of human health, from bone fractures to prostate cancer, cardiovascular disease, neuromuscular problems, and diabetes. Vitamin D is produced in the human body by the skin after sunlight absorption, but as human lifestyles change, so does the time of exposure to sunlight, necessitating dietary supplementation of vitamin D. Mushrooms have the advantages that they are the only source of vitamin D in the produce aisle and they are one of the few nonfortified food sources. Here, we review the current literature on enhancement of the vitamin D content in mushrooms and literature evidence on the bioavailability of vitamin D in humans and animals after ingesting ultraviolet (UV)-irradiated mushrooms. We also present available literature on health safety after UV irradiation of mushrooms, and we discuss issues arising in the attempt to incorporate UV irradiation into the mushroom production line.


Bioimpedance identifies body fluid loss after exercise in the heat: a pilot study with body cooling.
Assessment of post-exercise changes in hydration with bioimpedance (BI) is complicated by physiological adaptations that affect resistance (R) and reactance (Xc) values. This study investigated exercise-induced changes in R and Xc, independently and in bioelectrical impedance vector analysis, when factors such as increased skin temperature and blood flow and surface electrolyte accumulation are eliminated with a cold shower. Healthy males (n = 14, 24.1±1.7 yr; height (H): 182.4±5.6 cm, body mass: 72.3±6.3 kg) exercised for 1 hr at a self-rated intensity (15 BORG) in an environmental chamber (33°C and 50% relative humidity), then had a cold shower (15 min). Before the run BI, body mass, hematocrit and Posm were measured. After the shower body mass was measured; BI measurements were performed continuously every 20 minutes until R reached a stable level, then hematocrit and Posm were measured again. Compared to pre-trial measurements body mass decreased after the run and Posm, Hct, R/H and Xc/H increased (p<0.05) with a corresponding lengthening of the impedance vector along the major axis of the tolerance ellipse (p<0.001). Changes in Posm were negatively related to changes in body mass (r = -0.564, p = 0.036) and changes in Xc/H (r = -0.577, p = 0.041). Present findings showed that after a bout of exercise-induced dehydration followed by cold shower the impedance vector lengthened that indicates fluid loss. Additionally, BI values might be useful to evaluate fluid shifts between compartments as lower intracellular fluid loss (changed Xc/R) indicated greater Posm increase.


Serum thymidine kinase 1 correlates to clinical stages and clinical reactions and monitors the outcome of therapy of 1,247 cancer patients in routine clinical settings.
Thymidine kinase 1 in serum (STK1) has been found to be a reliable proliferation marker in clinical trials. In this study, we examined the significance of STK1 in routine clinical settings. The concentration of STK1 was determined by a sensitive dot blot ECL assay. The STK1 value was correlated to clinical stage and reactions and used for monitoring the outcome of surgery and/or multidrug chemotherapy of 1,247 patients with five different types of carcinomas (lung, esophagus, gastric, head and neck, and thyroid) in routine clinical settings. The STK1 values correlated with the clinical stage in patients with lung, esophagus, thyroid, and gastric carcinomas. After treatment, STK1 declined in all tumor groups after treatments (P < 0.01). The STK1 was low (<2 pM) or decreasing during treatment in patients with clinical reactions of complete response (CR) or partial response (PR), but high (>2 pM) or increasing in patients with stable disease (SD) or progressive disease (PD), some of them showing metastasis. STK1 also reflected the differences in clinical reactions when surgery and chemotherapy were compared. We concluded that the concentration of TK1 in serum correlates to clinical stages and clinical reactions and monitors the effect of tumor therapies, not only in controlled clinical trials, but also in routine clinical settings.


How calmodulin interacts with the adenosine A(2A) and the dopamine D(2) receptors.
Receptor heteromerization is a mechanism used by G protein-coupled receptors to diversify their properties and function. We previously demonstrated that these interactions occur through salt bridge formation between epitopes of the involved receptors. Recent studies claim that calmodulin (CaM) binds to an Arg-rich epitope located in the amino-terminus of the dopamine D(2) receptor third intracellular loop. This is the same epitope involved in adenosine A(2A)-D(2) receptor heteromerization, through Coulombic interaction between the Arg residues and a phosphorylated serine (pS) located in the medial segment of the C-terminus of the A(2A) receptor. Mass spectrometric analysis indicates that an electrostatic interaction involving the D(2) receptor Arg-rich epitope and several CaM acidic epitopes are mainly responsible for the D(2) receptor-CaM binding. CaM could also form multiple noncovalent complexes by means of electrostatic interactions with an epitope localized in the proximal segment of the C-terminus of the A(2A) receptor. Ca(2+) disrupted the binding of CaM to the D(2) but not to the A(2A) receptor epitope, and CaM disrupted the electrostatic interactions between the D(2) receptor epitope and the more distal A(2A) receptor epitope. A model is introduced with the possible functional implications of A(2A)-D(2)-CaM interactions. These in vitro findings imply a possible regulatory role for CaM in receptor heteromers formation.


Change in prevalence of IgE sensitization and mean total IgE with age and cohort.
Cross-sectional studies show that the prevalence of IgE sensitization is lower in older age groups than younger age groups. This could reflect either a decrease in sensitization with aging or a higher prevalence of sensitization in more recent birth cohorts. To assess change in IgE sensitization and mean total IgE in young adults as they age. Serum specific IgE to common allergens and total IgE were measured on 2 occasions about 9 years apart in 6371 young adults living in 28 centers, mainly in Western Europe, who took part in the European Community Respiratory Health Survey II. Outcomes were analyzed by using generalized estimating equations, and adjustments were made for differences between laboratory measures on the 2 occasions. Overall, there was no net change in the prevalence of sensitization to at least 1 of house dust mite, grass, or cat (net change per 10 years of follow-up, -0.1%; 95% CI, -1.7% to 1.5%), although there was a fall in mean total IgE (ratio of geometric mean total IgE, 0.86; 95% CI, 0.79 to 0.93). There was evidence that sensitization to at least 1 allergen was higher in more recent cohorts, and this was largely explained by a higher prevalence of sensitization to grass. The disease burden associated with IgE sensitization in adults, and particularly with IgE sensitization to grass, is likely to continue to increase for some time despite current evidence that the increase in allergy seen in children may have ceased.


Proteomics-based identification of outer-membrane proteins responsible for import of macromolecules in Sphingomonas sp. A1: alginate-binding flagellin on the cell surface.
A nonmotile gram-negative bacterium, Sphingomonas sp. A1, directly incorporates macromolecules such as alginate through a "super-channel" consisting of a pit formed on the cell surface, alginate-binding proteins in the periplasm, and an ATP-binding cassette transporter in the inner membrane. Here, we demonstrate the proteomics-based identification of cell-surface proteins involved in the formation of the pit and/or import of alginate. Cell-surface proteins were prepared from the outer membrane released as vesicles during the conversion of intact cells to spheroplasts. Seven proteins (p1-p7) with acidic isoelectric points were inducibly expressed in the outer membrane of strain A1 cells grown on alginate and showed significant identity with bacterial cell-surface proteins (p1-p4, TonB-dependent outer-membrane transporter; p5 and p6, flagellin; and p7, lipoprotein). Each mutant with a disruption of the p1-p4 or p6 gene showed significant growth retardation in the alginate medium. Flagellin homologues (p5 and p6) were further analyzed because strain A1 forms no flagellum. p5 was found to be uniformly distributed on the cell surface by immunogold-labeling electron microscopy and to exhibit alginate binding with a nanomolar dissociation constant by a surface plasmon resonance sensor. The cell surface of the p6 gene disruptant differed from that of the wild-type strain A1 in that pit formation was incomplete and cell-surface structures shifted from pleats to networks. These results suggest that, distinct from bacterial flagellins constituting a helical filament of flagella, strain A1 cell-surface flagellin homologues function as receptors for alginate and/or regulators of cell-surface structures.


Comparative effects of GnRH agonist therapy. Review of clinical studies and their implications.
To understand why differences in gonadotropin releasing hormone (GnRH) agonist therapeutic protocols may affect their efficacy and safety profiles, to understand the important study design facets regarding the literature on GnRH agonist treatment of endometriosis and to compare the efficacy and side effect profiles of FDA-approved GnRH agonist therapies used for the management of endometriosis and consider the implications. Review of the English-language literature regarding the use of GnRH agonists for the management of endometriosis. A limited number of studies are available that directly compare the effects of different GnRH agonists. However, contrary to medical opinion, it appears that there are significant differences between GnRH agonist therapies. The data suggest that it may be possible to reduce doses or alter regimens of GnRH agonists so as to reduce side effects while maintaining efficacy.


Effect of topical 5-aminosalicylic acid (5-ASA) therapy on rectal mucosal biopsy morphology in chronic ulcerative colitis.
Classic teaching emphasizes that chronic ulcerative colitis is characterized morphologically by the presence of fixed architectural and cellular mucosal changes that categorize the process as chronic. To examine the effect of topical 5-aminosalicylic acid (5-ASA) enemas on the presence of six histological features of chronicity in established chronic ulcerative colitis, 123 mucosal biopsies were taken prospectively at 1-month intervals, all from the same anatomic location (10 cm), from 14 patients treated with either 5-ASA or placebo enemas. The biopsies were evaluated for the presence of mixed inflammation in the lamina propria, crypt architectural abnormalities, basally located lymphoid aggregates, basal plasmacytosis, villiform surface epithelial configuration, and Paneth cell metaplasia. Overall, 29% of biopsies from 64% of patients were histologically normal (no chronic features, no active disease). Compared with patients treated with placebo enemas, patients treated with 5-ASA enemas showed a significantly higher percentage of normal biopsies (36% ASA group vs. 12% placebo group; p = 0.005) and a lower percentage occurrence of each individual histological feature of chronicity. In addition, patients treated with 5-ASA had a higher average number of normal biopsies per patient (3.0) than those treated with placebo enemas (1.3). Therefore, histologically normal-appearing mucosal biopsies do occur in established cases of chronic ulcerative colitis, and this finding is enhanced by treatment with 5-ASA enemas. Awareness of these results should prevent the presence of normal rectal mucosal biopsy findings in chronic ulcerative colitis patients from being misinterpreted as either evidence against this diagnosis or as representing focal skip areas characteristic of Crohn's disease.


Assessment of home-based behavior modification programs for autistic children: reliability and validity of the behavioral summarized evaluation.
Since the publication of Lovaas' (1987) impressive findings, there has been a proliferation of home-based behavior modification programs for autistic children. Parents and other paraprofessionals often play key roles in the implementation and monitoring of these programs. The Behavioral Summarized Evaluation (BSE) was developed for professionals and paraprofessionals to use in assessing the severity of autistic symptoms over the course of treatment. This paper examined the psychometric properties of the BSE (inter-item consistency, factorial composition, convergent validity, and sensitivity to parents' perceptions of symptom change over time) when used by parents of autistic youngsters undergoing home-based intervention. Recommendations for future research are presented.


Positive feedback regulation between adiponectin and T-cadherin impacts adiponectin levels in tissue and plasma of male mice.
Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.


Bringing cultured meat to market: Technical, socio-political, and regulatory challenges in cellular agriculture.
Cultured meat forms part of the emerging field of cellular agriculture. Still an early stage field it seeks to deliver products traditionally made through livestock rearing in novel forms that require no, or significantly reduced, animal involvement. Key examples include cultured meat, milk, egg white and leather. Here, we focus upon cultured meat and its technical, socio-political and regulatory challenges and opportunities. The paper reports the thinking of an interdisciplinary team, all of whom have been active in the field for a number of years. It draws heavily upon the published literature, as well as our own professional experience. This includes ongoing laboratory work to produce cultured meat and over seventy interviews with experts in the area conducted in the social science work. Cultured meat is a promising, but early stage, technology with key technical challenges including cell source, culture media, mimicking the in-vivo myogenesis environment, animal-derived and synthetic materials, and bioprocessing for commercial-scale production. Analysis of the social context has too readily been reduced to ethics and consumer acceptance, and whilst these are key issues, the importance of the political and institutional forms a cultured meat industry might take must also be recognised, and how ambiguities shape any emergent regulatory system.


A case report of human infection with lymphocytic choriomeningitis virus in Israel.
Lymphocytic choriomeningitis virus (LCMV) is an often-overlooked cause for viral meningitis but can have severe consequences in certain clinical situations. We present the first documented infection by LCMV in Israel. The epidemiology of LCMV is evolving with a potential for a worldwide endemicity due to the widespread presence of the natural host. Increased awareness and testing are required to identify this virus and screening of certain populations (e.g., organ donors) should be considered.


Location of positive surgical margin and its association with biochemical recurrence rate do not differ significantly in four different types of radical prostatectomy.
To analyze the location of the positive surgical margin (PSM) and its association with the biochemical recurrence (BCR) rate in cases of radical prostatectomy (RP) according to the type of surgery. We retrospectively analyzed 1,880 cases of RP. Baseline characteristics were analyzed. Locations of the PSM were recorded in the four surgery groups as apex, anterior, posterolateral, and base and were analyzed by using chi-square test. The association of the location of the PSM with the BCR rate was analyzed by using Kaplan-Meier survival analysis according to the type of surgery, which included radical perineal prostatectomy (RPP, n=633), radical retroperitoneal prostatectomy (RRP, n=309), laparoscopic radical prostatectomy (LRP, n=164), and robot-assisted laparoscopic radical prostatectomy (RALRP, n=774). A PSM was found in a total of 336 cases (18%): 122 cases of RPP (18%), 67 cases of RRP (17%), 29 cases of LRP (17%), and 119 cases of RALRP (15%). The PSM rate did not differ significantly by surgical type (p=0.142). The location of the PSM was the apex in 136 cases (7.2%), anterior in 67 cases (3.5%), posterolateral in 139 cases (7.3%), and base in 95 cases (5.0%), and showed no significant difference according to surgical type (p=0.536, p=0.557, p=0.062, and p=0.109, respectively). The BCR rate according to the location of the PSM did not differ significantly for the four types of surgery (p=0.694, p=0.301, p=0.445, and p=0.309 for RPP, RRP, LRP, and RALRP, respectively). The location of the PSM seemed to be unrelated to type of RP. There was no significant correlation between the BCR rate and the location of the PSM for any of the RP types.


Gestational Diabetes Mellitus Is Associated with Age-Specific Alterations in Markers of Adiposity in Offspring: A Narrative Review.
Maternal hyperglycemia alters an offspring's metabolic health outcomes, as demonstrated by the increased risk for obesity, impaired glucose handling and diabetes from early childhood onwards. Infant growth patterns are associated with childhood adiposity and metabolic health outcomes and, as such, can be used as potential markers to detect suboptimal metabolic development at an early age. Hence, we aimed to assess whether gestational diabetes mellitus (GDM) has an impact on offspring growth trajectories. Outcomes included weight gain (WG), body mass index (BMI), and skin fold thickness (SFT) measured at least at two time points from birth to later childhood. In addition, we explored the role of early life pre- and post-natal nutritional modifiable factors on longitudinal growth in infants of mother with GDM (GDM-F1). Despite the large heterogeneity of the studies, we can still conclude that GDM seems to be associated with altered growth outcomes in the offspring. More specifically, these alterations in growth outcomes seem to be rather time-specific. Increased SFT were reported particularly at birth, with limited information on reporting SFT between 2-5 y, and increased adiposity, measured via SFT and BMI, appeared mainly in later childhood (5-10 y). Studies evaluating longitudinal growth outcomes suggested a potential role of early life nutritional modifiable factors including maternal nutrition and breastfeeding. These may impact the cycle of adverse metabolic health by attenuating growth outcome alterations among GDM-F1. Conclusions: Timely diagnoses of growth deviations in infancy are crucial for early identification of GDM-F1 who are at risk for childhood overweight and metabolic disease development.


Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism.
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.


[Case of DYT1 dystonia (early-onset torsion dystonia) showing long-term focal dystonia in the arm].
DYTI dystonia (DYT1-D, early-onset torsion dystonia) is caused by a GAG deletion in the DYTI gene. Here we report a girl with child-onset familial DYT1-D showing localized arm involvement. The patient developed postural and action dystonia in the right and left arms at 7 and 9 years, respectively. She was misdiagnosed as hysteria due to lack of abnormalities on laboratory tests. At 11 years of age she was introduced to our clinic. Increased muscle tonus and dystonic discharges seen on surface electromyogram in the right arm and the sternocleidomastoid muscle led to the diagnosis of dystonia. A GAG deletion in the DYTI gene was confirmed in the patient, her healthy father and paternal grandfather with torsion dystonia. Titration of levodopa resulted in the fluctuation of her arm dystonia. Combined therapy by levodopa and trihexyphenidyl relieved postural dystonia in the right arm but not action dystonia in the left. Both types of dystonia in the right and left arms were well ameliorated by the additional increase of levodopa. Somatosensory evoked potentials demonstrated abnormal premovement gating. The latency and accuracy of the amplitude were disturbed in visually guided saccadic eye movement. Now at more than 11 years after onset, the patient has not shown torsion or involvement of the lower extremities. Most DYT1-D patients are refractory to medication and early surgical intervention is recommended. However, the presence of DYT1-D patients showing a milder disease course should also be considered.


Improved Cardiovascular and Cardiometabolic Risk in Patients With Type 1 Diabetes and Autoimmune Polyglandular Syndrome Switched From Glargine to Degludec Due to Hypoglycaemic Variability.
Background: Cardiovascular disease is a frequent complication of type 1 diabetes (T1D). We evaluated the effectiveness of switching from glargine to degludec in reducing the cardiovascular risk factors, the Framingham risk score (FRS) and visceral adiposity index (VAI) in patients with T1D and autoimmune polyglandular syndrome (APS). Methods: We selected 66 T1D outpatients who had been on stable treatment with glargine for at least 5 years. Among them, 30 patients maintained glargine (group A), while 36 were switched to degludec (group B) for 12 months. At baseline and after 12 months of observation, clinical and metabolic parameters, insulin dose, 30-days blood glucose (BG) self monitoring, VAI and FRS were obtained. Results: At baseline, patients in group B had more hypoglycaemic episodes and prevalence of hypertension than those in group A. After 12 months on degludec, patients in group B had a significant decrease in BMI (p = 0.003), waist circumference (p < 0.001), total daily insulin as U/day and U/kg (p = 0.001 for both), basal insulin as U/day and U/kg (p = 0.001 for both), HbA1c (p < 0.001), mean (p = 0.035) and standard deviation of daily BG (p = 0.017), mean pre-meal BG (p = 0.016), number of hypoglycaemic episodes (p = 0.001), VAI (p = 0.012) and FRS (p = 0.019) and a significant increase in HDL-C (p < 0.001), compared to baseline. At 12 months of treatment a significant decrease in BMI (p = 0.017), WC (p = 0.003), SBP (p = 0.001), DBP (p = 0.005), basal insulin as U/day (p = 0.018) and U/kg (p = 0.045), HbA1c (p = 0.040) and FRS (p = 0.010) was observed in group B compared to group A. Conclusions: Our preliminary data suggest that 12 months' treatment with degludec is associated with an improvement of glycaemic control, cardiometabolic and cardiovascular risk, compared to glargine, in patients with T1D and APS.


Content validity of the WorkHab functional capacity evaluation.
Validity is a dynamic process and as part of a continual process of evaluation of tools, this study aimed to evaluate content validity of the WorkHab functional capacity evaluation, a tool used in occupational rehabilitation. A cross sectional survey of health professionals who conduct FCEs investigated their ratings of item relevance and item difficulty across different categories of work and injuries. The survey also explored the relationship of the WorkHab FCE items with the physical demand items of the Dictionary of Occupational Titles (DOT). The majority of items of the WorkHab FCE were rated as relevant for manual work and vocational retraining with over 90% agreement between the 106 respondents. Therapists identified the WorkHab items of climbing, crawling and balance as less relevant for sedentary work. Lifting items were perceived as the most difficult for those with a lower back injury, or an upper limb injury. Sixteen of the 18 WorkHab FCE items had 100% agreement with the equivalent items on the DOT. The WorkHab FCE items that had poor agreement with the DOT were mainly sensory items such as see, feel, talk and hear. The findings of this study support the content validity for the WorkHab FCE specifically in relation to manual work and for vocational retraining purposes.


Incidence of breast cancer in a cohort of 5,135 transgender veterans.
Transgender (TG) persons often receive, or self-treat, with cross-sex hormone (CSH) treatments as part of their treatment plans, with little known about their incidence of breast cancer. This information gap can lead to disparities in the provision of transgender health care. The purpose of the study was to examine the incidence of breast cancer in the largest North American sample of TG patients studied to date to determine their exposure to CSH, incidence of breast cancer, and to compare results with European studies in transsexual populations. We used Veterans Health Administration (VHA) data from 5,135 TG veterans in the United States from 1996 to 2013 to determine the incidence of breast cancer in this population. Chart reviews were completed on all patients who developed breast cancer. Age-standardized incidences of breast cancer from the general population were used for comparison. Person-years of exposure to known CSH treatment were calculated. Ten breast cancer cases were confirmed. Seven were in female-to-male patients, two in male-to-female patients, and one in a natal male with transvestic fetishism. Average age at diagnosis was 63.8 (SD = 8.2). 52 % received >1 dose of CSH treatment from VHA clinicians. All three males presented with late-stage disease were proved fatal. The overall incidence rate was 20.0/100,000 patient-years of VHA treatment (95 % CI 9.6-36.8), irrespective of VA CSH treatment. This rate did not differ from the expected rate in an age-standardized national sample, but exceeded that reported for smaller European studies of transsexual patients that were longer in duration. Although definitive conclusions cannot be made regarding breast cancer incidence in TG veterans who did or did not receive VA CSH due to the sample size and duration of observation, it appears that TG veterans do not display an increase in breast cancer incidence. This is consistent with European studies of longer duration that conclude that CSH treatment in gender dysphoric patients of either birth sex does not result in a greater incidence than the general population.


Retrospective study comparing two materials commonly used in the LFS technique for CCLR.
Cranial cruciate ligament rupture (CCLR) is the most common cause of degenerative joint disease (DJD) in the stifle of adult dogs. Over the last several years, a new generation of nonabsorbable, multifilament, polyblend polyethylene orthopedic suture materials have been evaluated for use in the lateral fabellar suture (LFS) technique for surgical treatment of CCLR. This retrospective study compared the short-term outcome of 16 dogs that were treated using the LFS technique using either a proprietary polyblend polyethylene orthopedic suture material (FW) or monofilament nylon leader line (NLL). The FW was significantly more likely to fail compared with the NLL (P = 0.0379). Specifically, the FW was 14.667 times likelier to fail than the NLL. When one and two strands of NLL were compared with FW, the FW was 6 times more likely to fail than one strand of NLL and 32 times more likely to fail than two strands of NLL. To the authors' knowledge, this is the first study comparing the two materials used in the LFS procedure performed in clinical cases.