Allergenicity of an enzymatic hydrolysate of soybean 2S protein.
This study was performed to examine how the characteristics of soybean 2S protein influence allergenicity after enzymatic hydrolysis. Soybean 2S protein was extracted and enzymatic hydrolysis was performed using pepsin and chymotrypsin. Allergenicity was observed using soybean-sensitive patients' sera. Only 13.3% (6/45) of soybean-sensitive patients reacted to soybean Kunitz trypsin inhibitor (SKTI), known as the major allergen of soybean 2S protein. After peptic hydrolysis for 90 min at pH 1.2, the intensity of SKTI decreased to 25% but was still visible on SDS-PAGE. Chymotryptic hydrolysis following peptic hydrolysis at pH 8 for 60 min showed a limited hydrolytic effect on soybean 2S protein. Peptic hydrolysis of soybean 2S protein partially reduced the allergenicity of soybean 2S protein, while chymotryptic hydrolysis following peptic hydrolysis increased slightly the allergenicity. Food allergy caused by soybean 2S protein occurred in part of the soybean-sensitive patients. SKTI was partially digested after peptic hydrolysis for 90 min. The allergenicity was decreased with peptic hydrolysis, while subsequent treatment of chymotrypsin increased slightly the allergenicity.


Respiratory patterns during sleep in Down's syndrome:importance of central apnoeas.
Obstructive sleep apnoea episodes have been reported repeatedly in Down's syndrome (DS) patients as a consequence of the presence of predisposing malformations or intercurrent pathology of the upper airways. There are no data on respiratory patterns of uncomplicated Down's syndrome subjects. In order to evaluate the eventual effects of central nervous system (CNS) impairment on respiration in DS, we studied the respiratory patterns during sleep of a group of 10 DS subjects, aged 8.6-32.2 y, without relevant upper airway pathology. In order to control the possible effects of sleep structure and mental retardation on the results obtained, we compared the findings in DS with those obtained from a group formed by subjects affected by fragile X syndrome (six males and one female, aged 10.0-15.42 y) another genetically determined type of mental retardation. Sleep structure was similar in both groups; however, DS subjects showed significantly higher indices of central sleep apnoea and of oxygen desaturation than fragile X patients (P < 0.005). As far as DS individuals were considered, a significant preponderance of central, as opposed to obstructive, sleep apnoeas was found (89.4% vs. 9.4%, respectively; 1.2% were mixed) which showed a significant age-related increase. Central respiratory pauses were mostly preceded by sighs, which occurred more frequently during sleep stages 1 and REM, and were often organized in long sequences of periodic-like breathing. During REM sleep, they were less frequently preceded by sighs and by body movements than during NREM sleep. Obstructive sleep apnoeas occurred more often during REM sleep and were more rarely preceded by sighs or by body movements. Both central and obstructive apnoeas induced significant oxygen desaturation in 50-69.6%. Sleep structure was not significantly modified by apnoeas and oxygen desaturation. We hypothesize that the increase in central sleep apnoeas is related to a dysfunction of the central respiratory control at a brainstem level in DS.


[Environmental studies of asymptomatic kindergarten children as carriers of enterohemorrhagic Escherichia coli (EHEC) in the Ammerland district].
The increase of serious EHEC diseases in the northwest Lower Saxony in summer 1997 was accompanied by a lively discussion on the hazard represented by this pathogen which gained a large amount of media attention. The Lower Saxony Public Health Department initiated a study of this case in the Weser-Ems government district to investigate the spread of EHEC by children and their supervisors in kindergartens receiving certified raw milk supply. This established that there were ten kindergarten children in the Ammerland rural district who were asymptomatik EHEC carriers. The Local Public Health Department immediately carried out the necessary epidemic hygiene measures. First of all, control investigations were performed on the affected children, including environmental investigations on their families and contracts. The results of these investigations revealed the need to carry out additional environmental investigations in two kindegartens (follow-up investigations) as well as amongst employees in a hospital canteen. Within the families, a mother of an affected child was also identified as another asymptomatic EHEC carrier. However, the strains that were isolated reflected different serotypes. In total, the investigation of 337 people in contact with the eleven asymptomatic EHEC carriers did not confirm any person-to-person transmission--even though three of the kindergarten children shedding the organisms for 6-10 weeks attended the kindergartens for at least 4 weeks. No EHEC disease occurred in the communal facilities, neither were any positive cases identified by additional control investigations. The results indicate a probable lower rate of infectiousness by healthy EHEC carriers than was previously thought to be the case. Further studies are needed to decide if in future one should proceed on a case by case basis when considering the reauthorization of affected children and other people to enter communal facilities.


Knockdown of zif268 in the Posterior Dorsolateral Striatum Does Not Enduringly Disrupt a Response Memory of a Rewarded T-Maze Task.
Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like 'response' memory, but not an instrumental goal-directed 'place' memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories.


Vocabulary and Main Idea Reading Intervention Using Text Choice to Improve Content Knowledge and Reading Comprehension of Adolescents With Autism Spectrum Disorder.
This simultaneous replication single-case design study investigated a vocabulary and main idea intervention with an aspect of text choice provided to students with autism spectrum disorder (ASD). Five middle school students with ASD participated in two instructional groups taught by school-based personnel. Results were initially mixed. These results were followed by upward and stable trends, indicating a functional relationship between the independent and dependent variables. Social validity measures indicated that students appreciated the opportunity to make choices on text selection.


Breath ethane peaks during a single haemodialysis session and is associated with time on dialysis.
There is growing evidence that oxidative stress is increased in haemodialysis patients and that dialysis per se is a contributory factor. The elevated oxidant stress, a result of increased production of reactive oxidant species (ROS), may be due to increased pro-inflammatory activity and reduced antioxidant mechanisms. ROS are transitory molecules and therefore surrogate markers of oxidant damage are required. Identification of potential causes of oxidative damage such as dialyser membranes or dialysate has been proposed and therefore assessment of oxidative damage during a single dialysis session would be of interest. We have used breath ethane, a widely accepted marker of oxidative stress, to investigate the cause and extent of the resulting oxidative damage during single dialysis sessions. Our study involved assessment of breath ethane levels during haemodialysis in an end-stage renal failure haemodialysis population (n = 24). Breath samples were collected using discrete sampling techniques and were subsequently analysed using laser spectroscopy. Each patient adopted the role of longitudinal control in this study and his or her breath ethane level was monitored regularly during the dialysis session. Significant breath ethane elevation was observed at the beginning (within the first 10 min) of each dialysis session. This paper provides an in-depth statistical analysis and clinical discussion of the recent findings. A regression analysis of the collected breath ethane data showed a trend towards increased ethane levels for patients on dialysis for a shorter duration of time (r = 0.656, R-Sq = 43.3%, p = 0.001). Multiple linear regression was undertaken to further assess these associations and revealed that peak ethane levels were significantly and independently associated with time period on dialysis (p < 0.000), vascular access (p = 0.013) and male sex (p = 0.005). However, whilst diabetes status had demonstrated a correlation with peak ethane levels (0.525, p = 0.008) this was not independent of vascular access status. This multivariate linear model was significantly associated with Ln peak ethane levels (S = 0.744, R-Sq = 80.8%). The observed rapid rise in oxidative stress during the first few minutes after commencement of dialysis gives new insight into the dynamics of the oxidative damage resulting from dialysis treatment.


Considerations When Performing Arthrodesis in the Scleroderma Hand.
Hand deformities secondary to scleroderma can limit activities of daily living and be associated with substantial disability. This study aimed to evaluate the outcomes following arthrodesis performed to treat digital contractures secondary to scleroderma. We performed a retrospective review of all patients with scleroderma who underwent arthrodesis by a single surgeon from 2015 to 2020. We collected demographic information, operative variables, and outcomes variables. Our primary outcome was occurrence of any postoperative complication, which we defined to include wound dehiscence, digital ischemia, malunion, nonunion, cellulitis, and osteomyelitis. We calculated descriptive statistics and performed all analyses at the joint level. We identified 9 patients who underwent arthrodesis of 19 joints. All patients were women with a mean age of 55.3 years. At the time of surgery, most patients were taking disease-modifying antirheumatic drugs (DMARDs). Kirschner wires (K-wires) were used in most cases (n = 18), 15 of which were removed uneventfully at an average of 4.8 months after surgery. With a mean follow-up time of 15.4 months, the overall complication rate was 5.3% (n = 1). This patient developed digital ischemia in 1 of 4 operative digits, which became gangrenous and required amputation. Our study suggests that arthrodesis can be performed safely in the scleroderma hand, even when patients are taking DMARDs. Given the uneventful K-wire removal in all joints and the high risk of exposure of buried hardware in this population, we recommend nonpermanent placement of K-wires. Hand surgeons may consider arthrodesis in the scleroderma hand before proceeding to revision amputation.


[MALT lymphoma of the parotid gland associated with Sjögren syndrome. A case report and review of literature].
Sjögren syndrome (SS) is a chronic inflammatory process involving the exocrine glands. Its association with the development of lymphomas is well documented, and this risk has estimated to be 44 times that of the general population. A MALT lymphoma of the parotid gland in a patient with Sjögren syndrome is reported. We review the literature and comment the clinical and histopathological features of these tumors.


Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models.
In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 μg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 μg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2-deficient tissues.


Distinct functional properties of IkappaB alpha and IkappaB beta.
The biological activity of the transcription factor NF-kappaB is controlled mainly by the IkappaB alpha and IkappaB beta proteins, which restrict NF-kappaB to the cytoplasm and inhibit its DNA binding activity. Here, we carried out experiments to determine and compare the mechanisms by which IkappaB alpha and IkappaB beta inhibit NF-kappaB-dependent transcriptional activation. First, we found that in vivo IkappaB alpha is a stronger inhibitor of NF-kappaB than is IkappaB beta. This difference is directly correlated with their abilities to inhibit NF-kappaB binding to DNA in vitro and in vivo. Moreover, IkappaB alpha, but not IkappaB beta, can remove NF-kappaB from functional preinitiation complexes in in vitro transcription experiments. Second, we showed that both IkappaBs function in vivo not only in the cytoplasm but also in the nucleus, where they inhibit NF-kappaB binding to DNA. Third, the inhibitory activity of IkappaB beta, but not that of IkappaB alpha, is facilitated by phosphorylation of the C-terminal PEST sequence by casein kinase II and/or by the interaction of NF-kappaB with high-mobility group protein I (HMG I) on selected promoters. The unphosphorylated form of IkappaB beta forms stable ternary complexes with NF-kappaB on the DNA either in vitro or in vivo. These experiments suggest that IkappaB alpha works as a postinduction repressor of NF-kappaB independently of HMG I, whereas IkappaB beta functions preferentially in promoters regulated by the NF-kappaB/HMG I complexes.


Effects of acridine orange on the growth of Escherichia coli.
Exposure of Escherichia coli to critical acridine orange (AO) concentrations did not result in loss of viability. However, the deoxyribonucleic acid (DNA) of cells exposed to such agents was rapidly degraded and repolymerized. On the other hand, a bacterium deficient in DNA repair (pol A(1) (-), lacking DNA polymerase) was sensitive to the action of AO. The DNA of such cells was also degraded but it was not repaired.


Autoreactive T cells in mercury-induced autoimmune disease: in vitro demonstration.
Mercuric chloride induces in Brown-Norway rats an autoimmune disease due to a T dependent polyclonal activation of B cells. Various autoantibodies and a striking increase in total serum IgE level are observed as consequences of this polyclonal activation. The aim of this study was to investigate the in vitro response of autologous syngeneic normal lymphocytes to lymphocytes exposed in vivo or in vitro to HgCL2. Helper/inducer T cells (W3/25 +) exposed to HgCl2 were found to stimulate normal T lymphocytes in the presence of normal Ia (+) cells. The proliferating T cells also had the helper/inducer phenotype. To demonstrate the potential relevance of this in vitro phenomenon to the autoimmune disease, HgCl2-pretreated T cells were injected into the footpads of normal syngeneic recipients. Draining popliteal lymph nodes contained a highly significant number of both surface IgE positive and IgE containing cells. These experiments demonstrate that HgCl2 induces autoreactive T cells and suggest that these cells may be responsible for the autoimmune disease.


On Five- vs Six-membered Diacetal Formation from Threitol and the Intermediacy of Unusually Stable Protonated Species(1).
The long known, but hitherto poorly understood, thermodynamically controlled diacetalation of rac-threitol with alkylaldehydes provided bicyclic, cis-tetraoxadecalin (TOD) ("66") and bi(dioxolanyl) (BDO) ("55") products, shown to be formed in acid-concentration and temperature-dependent ratio. The configurational and conformational isomeric diacetals obtained in four such reactions of substituted aldehydes (RCHO, R = CH(3), CH(2)Cl, CH(2)Br, CO(2)CH(3)) with rac-threitol were isolated and characterized. A variable acid-concentration analysis of the equilibrium mixture of products in one such case (R = CH(2)Br) was performed and provided equilibrium constants and, hence, free-energy differences among these products and their relatively stable protonated intermediates. The latter were rationalized by the unusually high proton-affinity calculated for the cis-TOD ("66") form.


Overexpressed Tomosyn Binds Syntaxins and Blocks Secretion during Pollen Development.
SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) complex formation is necessary for intracellular membrane fusion and thus has a key role in processes such as secretion. However, little is known about the regulatory factors that bind to Qa-SNAREs, which are also known as syntaxins (SYPs) in plants. Here, we characterized Arabidopsis (Arabidopsis thaliana) Tomosyn protein (AtTMS) and demonstrated that it is a conserved regulator of SYPs in plants. AtTMS binds strongly via its R-SNARE motif-containing C terminus to the Qa domain of PM-resident, pollen-expressed SYP1s (SYP111, SYP124, SYP125, SYP131, and SYP132), which were narrowed down from 12 SYPs. AtTMS is highly expressed in pollen from the bicellular stage onwards, and overexpression of AtTMS under the control of the UBIQUITIN10, MSP1, or LAT52 promoter all resulted in defective pollen after the microspore stage in which secretion was inhibited, leading to the failure of intine deposition and cell plate formation during pollen mitosis I. In tobacco (Nicotiana benthamiana) leaf epidermal cells, overexpression of AtTMS inhibited the secretion of secreted GFP. The defects were rescued by mCherry-tagged SYP124, SYP125, SYP131, or SYP132. In vivo, SYP132 partially rescued the pMSP1:AtTMS phenotype. In addition, AtTMS, lacking a transmembrane domain, was recruited to the plasma membrane by SYP124, SYP125, SYP131, and SYP132 and competed with Vesicle-Associated Membrane Protein721/722 for binding to, for example, SYP132. Together, our results demonstrated that AtTMS might serve as a negative regulator of secretion, whereby active secretion might be fine-tuned during pollen development.


Plus- and minus-end directed microtubule motors bind simultaneously to herpes simplex virus capsids using different inner tegument structures.
Many viruses depend on host microtubule motors to reach their destined intracellular location. Viral particles of neurotropic alphaherpesviruses such as herpes simplex virus 1 (HSV1) show bidirectional transport towards the cell center as well as the periphery, indicating that they utilize microtubule motors of opposing directionality. To understand the mechanisms of specific motor recruitment, it is necessary to characterize the molecular composition of such motile viral structures. We have generated HSV1 capsids with different surface features without impairing their overall architecture, and show that in a mammalian cell-free system the microtubule motors dynein and kinesin-1 and the dynein cofactor dynactin could interact directly with capsids independent of other host factors. The capsid composition and surface was analyzed with respect to 23 structural proteins that are potentially exposed to the cytosol during virus assembly or cell entry. Many of these proteins belong to the tegument, the hallmark of all herpesviruses located between the capsid and the viral envelope. Using immunoblots, quantitative mass spectrometry and quantitative immunoelectron microscopy, we show that capsids exposing inner tegument proteins such as pUS3, pUL36, pUL37, ICP0, pUL14, pUL16, and pUL21 recruited dynein, dynactin, kinesin-1 and kinesin-2. In contrast, neither untegumented capsids exposing VP5, VP26, pUL17 and pUL25 nor capsids covered by outer tegument proteins such as vhs, pUL11, ICP4, ICP34.5, VP11/12, VP13/14, VP16, VP22 or pUS11 bound microtubule motors. Our data suggest that HSV1 uses different structural features of the inner tegument to recruit dynein or kinesin-1. Individual capsids simultaneously accommodated motors of opposing directionality as well as several copies of the same motor. Thus, these associated motors either engage in a tug-of-war or their activities are coordinately regulated to achieve net transport either to the nucleus during cell entry or to cytoplasmic membranes for envelopment during assembly.


Temperament and early environmental influences in kleptomania.
The purpose of this investigation was to shed light on the temperament and early life experiences of people suffering from kleptomania. Twelve outpatients (five men [41.6%]; seven women [58.3%]; mean age, 39.6 +/- 11.0 years) who met DSM-IV criteria for kleptomania and had no other axis I disorders by Structured Clinical Interview for DSM-IV (SCID) completed the Tridimensional Personality Questionnaire (TPQ) and the Parental Bonding Instrument (PBI). Patients with kleptomania had significantly higher novelty-seeking scores (P =.001), higher harm-avoidance scores (P =.005), and lower reward-dependence scores (P =.023) than normal controls. The kleptomania subjects had significantly lower maternal and paternal care scores, and lower maternal protection scores, than the normative values (P <.05). Neither TPQ nor PBI scores correlated with illness severity. These findings suggest that an understanding of early parenting behavior and a dimensional approach to the personality of kleptomaniacs may offer insight into this disorder and provide clues to treatment strategies.


The Increased Expression of Matrix Metalloproteinase-9 Messenger RNA in the Non-lesional Skin of Patients with Large Plaque Psoriasis Vulgaris.
A difference of the interleukin-18 (IL-18) mRNA expression among several proinflammatory genes was previously observed between large plaque (LP) psoriasis patients (more than 5 cm lesions are typical) and small plaque (SP) psoriasis patients (1~2 cm lesions are typical). Therefore, it is necessary to test whether there is any difference in the expression of the genes that activate IL-18 or the expression of genes that are induced by IL-18. To test the differential mRNA expressions of caspase-1, STAT-6, MMP-1, MMP-2, MMP-9 and TIMP-1 according to the clinical types of psoriasis vulgaris lesions in Korean patients, we have analyzed the skin samples of psoriasis vulgaris patients. The total cellular RNA of skin samples from groups of patient with LP and SP psoriasis was analyzed by performing real-time PCR (the Taqman method) to compare the differences in the mRNA expressions. The caspase-1 and STAT-6 mRNA expression levels from the SP lesional skin of the patients were increased compared with the caspase-1 and STAT-6 mRNA expression levels from SP non-lesional skin or normal skin, but these expression levels from the SP non-lesional skin were not significantly different from those of the LP non-lesional skin. Among MMP-1, MMP-2, MMP-9 and TIMP-1, the expressions of MMP-1, MMP-2 and MMP-9 mRNA were increased in the SP lesional skin compared with those of the SP non-lesional skin. The MMP-1 mRNA expressions in both the LP and SP lesional skin were increased compared with those in the normal skin (p=0.028 and p=0.007 respectively). The MMP-9 mRNA expression in the LP non-lesional skin was elevated compared with the MMP-9 mRNA expression in the SP non-lesional skin (p=0.047). The TIMP-1 mRNA expression levels from the non-lesional skin and the lesional skin of the psoriasis patients and the normal skin samples were not significantly different. The increased expression of MMP-9 mRNA in the LP non-lesional skin compared to that of the SP non-lesional skin in the psoriatic skin suggests that the increased MMP-9 mRNA expression is related to the large size type of lesion.


Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice.
The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.


[Digestive system status after prolonged space flights].
In the crewmembers of four Salyut-6 long-term flights, enzyme excretory function of the gastro-intestinal tract was investigated. These studies included: gastric proenzyme, pepsinogen, and pancreatic enzymes, amylase and lipase, in blood and urine, trypsin in blood, intestinal enzymes, invertase and glycyl-L-leucine dipeptidase in feces, and lipids in feces. The results obtained demonstrated a correlation between changes in enzyme excretion and space flight duration and profile. After the 140- and 175-day flight the most marked changes in the digestive organs were seen; they manifested as a simultaneous increase in secretory function of the stomach and the pancreas. However, after the 185-day flight, in which advanced countermeasures were used, the above changes were less distinct.


Revision anterior cruciate ligament reconstruction using the lateral third of the ipsilateral patellar tendon after failure of a central-third graft: a preliminary report on 10 patients.
Long-term outcomes were reported for 10 (77%) of 13 cases of revision anterior cruciate ligament (ACL) reconstruction using the lateral third of the ipsilateral patellar tendon as a graft. All primary ACL reconstructions were ipsilateral central-third bone-patellar tendon-bone graft procedures. Mean age at follow-up was 30.7 years, and mean time from revision ACL surgery to follow-up was 42.9 months. At follow-up, average KT-1000 difference between knees was 2.4 mm. All patients had a negative pivot shift, extension within 5 degrees of the contralateral knee, and flexion within 15 degrees. Mean bilateral comparison ratios for isokinetic strength and hop testing were: extension, 83.5%; flexion, 96%; and single-leg hop 96.9%. No patella fractures or tendon ruptures had occurred. All patients had returned to their previous work level, and 8 of the 10 patients could participate in at least "moderate" sports activities (e.g., skiing and tennis). The results were comparable to published outcome reports for both primary and revision ACL reconstruction. The lateral third of the ipsilateral patellar tendon is a good graft option for revision ACL reconstruction.


Quantum interference of electrically generated single photons from a quantum dot.
Quantum interference lies at the foundation of many protocols for scalable quantum computing and communication with linear optics. To observe these effects the light source must emit photons that are indistinguishable. From a technological standpoint, it would be beneficial to have electrical control over the emission. Here we report of an electrically driven single-photon source emitting indistinguishable photons. The device consists of a layer of InAs quantum dots embedded in the intrinsic region of a p-i-n diode. Indistinguishability of consecutive photons is tested in a two-photon interference experiment under two modes of operation, continuous and pulsed current injection. We also present a complete theory based on the interference of photons with a Lorentzian spectrum which we compare to both our continuous wave and pulsed experiments. In the former case, a visibility was measured limited only by the timing resolution of our detection system. In the case of pulsed injection, we employ a two-pulse voltage sequence which suppresses multi-photon emission and allows us to carry out temporal filtering of photons which have undergone dephasing. The characteristic Hong-Ou-Mandel 'dip' is measured, resulting in a visibility of 64 +/- 4%.


Prevalence of masturbation and associated factors in a British national probability survey.
A stratified probability sample survey of the British general population, aged 16 to 44 years, was conducted from 1999 to 2001 (N = 11,161) using face-to-face interviewing and computer-assisted self-interviewing. We used these data to estimate the population prevalence of masturbation, and to identify sociodemographic, sexual behavioral, and attitudinal factors associated with reporting this behavior. Seventy-three percent of men and 36.8% of women reported masturbating in the 4 weeks prior to interview (95% confidence interval 71.5%-74.4% and 35.4%-38.2%, respectively). A number of sociodemographic and behavioral factors were associated with reporting masturbation. Among both men and women, reporting masturbation increased with higher levels of education and social class and was more common among those reporting sexual function problems. For women, masturbation was more likely among those who reported more frequent vaginal sex in the last four weeks, a greater repertoire of sexual activity (such as reporting oral and anal sex), and more sexual partners in the last year. In contrast, the prevalence of masturbation was lower among men reporting more frequent vaginal sex. Both men and women reporting same-sex partner(s) were significantly more likely to report masturbation. Masturbation is a common sexual practice with significant variations in reporting between men and women.


Olfaction and its alteration by nasal obstruction, rhinitis, and rhinosinusitis.
The sense of smell has been largely ignored by otorhinolaryngologists, even though 1) its medical stewardship falls within their specialty's purview, 2) olfactory dysfunction is not uncommon in the general population, and 3) disorders of olfaction have significant quality of life, nutritional, and safety consequences. This report provides a succinct overview of the major intranasal neural systems present in humans (namely, cranial nerves O, I, and V, and the nonfunctional accessory [vomeronasal] organ system), along with a summary of notable findings resulting from the application of modern olfactory tests to patient populations, emphasizing diseases of the nose. Such tests have led to the discovery of significant influences of age, gender, smoking, toxic exposure, and genetics on the ability to smell. Within the field of otorhinolaryngology, they have revealed that 1) surgical and medical interventions in patients with rhinosinusitis do not, on average, lead to complete recovery of olfactory function, despite common beliefs to the contrary, and 2) associations are generally lacking between measures of airway patency and olfactory function in such cases. These findings have thrown into question the dogma that olfactory loss in rhinosinusitis is attributable primarily to blockage of airflow to the receptors and have led to histopathological studies demonstrating significant olfactory epithelial compromise in sinonasal syndromes.


A study of Staphylococcus aureusnasal carriage, antibacterial resistance and virulence factor encoding genes in a tertiary care hospital, Kayseri, Turkey.
This study was to determine the virulence encoding genes, and the antibiotic resistance patterns of the Staphylococcus aureus isolates, which were isolated from the nasal samples of chest clinic patients. The nasal samples of the in-patients (431) and out-patients (1857) in Kayseri Training and Research Hospital's Chest Clinic, Kayseri, Turkey, were cultured on CHROMagar (Biolife, Italiana) S. aureus, and subcultured on sheep blood agar for the isolation of S. aureus. Disc diffusion method was used for antimicrobial susceptibility testing. The occurrence of the staphylococcal virulence encoding genes (enterotoksins [sea, seb, sec, see, seg, seh, sei, sej], fibronectin-binding proteins A, B [fnbA, fnbB], toxic shock syndrome toxin-1 [tst]) were detected by polymerase chain reaction. Forty-five of the 55 (81.8%) S. aureus isolates from inpatients, and 319 (90.6%) isolates from tested 352 out-patient's isolates were suspected to all the antibiotics tested. methicillin-resistant S. aureus (MRSA) was detected in 1.2% of S. aureus isolates. Rifampin, trimethoprim-sulfamethoxazole, clindamycin, erythromycin, gentamicin resistance rates were 1.2%, 1.7%, 2.0%, 8.8%, and 1.2%, respectively. The isolates were susceptible to teicoplanin and vancomycin. The genes most frequently found were tst (92.7%), seg (85.8%), sea (83.6%), fnbA (70.9%). There was no statistical significance detected between MRSA and mecA-negative S. aureus isolates in encoding genes distribution (P > 0.05). Our results show that virulence factor encoding genes were prevalent in patients with S. aureus carriage, whereas antibiotic resistance was low. These virulence determinants may increase the risk for subsequent invasive infections in carriers.


Trismus following radiotherapy to the head and neck is likely to have distinct genotype dependent cause.
Trismus frequently occurs as a consequence of radiotherapy or chemo-radiotherapy to the head and neck, with a loss of function that can reduce the overall quality of life. Radiation can trigger an intense fibrosis within the masticatory muscles and transforming growth factor beta 1 (TGF β1) is involved in this process. As in other tissues the degree of fibrosis may be related to a single nucleotide polymorphism; C-T at position -509 in the TGF β1 gene. Trismus was measured in 62 patients before and after radiotherapy or chemoradiotherapy, blood was taken for DNA extraction, and genotype analysis of the TGF β1 gene. Trismus was analysed against, patient age, sex, tumour site and stage, radiotherapy, and chemotherapy. After radiotherapy or chemo-radiotherapy the reduction in mouth opening was shown to be significantly related to the presence of the T allele (p<0.001), with patients homozygous the most likely to be severely affected. No other patient, tumour or treatment factors were significant. Hence the TGF β1 genotype is likely to be an important predictor of the degree of post radiotherapy or chemo-radiotherapy trismus.


Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor.
Recent in vitro studies have shown that fibrinolytic activity may be attenuated by a thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin, generated via the intrinsic pathway of coagulation in a factor XI-dependent way. Thus factor XI may play a role in the regulation of endogenous fibrinolysis. The aim of this study was to investigate the effect of in vivo inhibition of factor XI and TAFI in an experimental thrombosis model in rabbits. Incorporation of anti-factor XI antibodies in jugular vein thrombi resulted in an almost twofold increase in endogenous thrombolysis compared with a control antibody. A similar effect was observed when the anti-factor XI antibody was administered systemically. Inhibition of TAFI activity also resulted in a twofold increase in clot lysis whereas inhibition of both factor XI and TAFI activity had no additional effect. Thus, we provide the first in vivo evidence for enhanced thrombolysis through inhibition of clotting factor XI, demonstrating a novel role for the intrinsic pathway of coagulation. Furthermore we demonstrate that inhibition of TAFI had a similar effect on thrombolysis. We postulate that inhibition of factor XI activity enhances thrombolysis because of diminished indirect activation of TAFI.


Mechanism of prolactin action.
Most experimental information regarding the mechanism of action of prolactin in its diverse array of target tissues has been discovered using mammary tissues. Evidence has recently been presented that suggests that prolactin may be "internalized" into its target cells and have intracellular actions. Accordingly, it has been reported that prolactin stimulates RNA synthesis in isolated nuclei from mammary tissues; and by immunoflorescent studies, prolactin has been located within its target cells. It has been further suggested from additional experimental studies that the primary action of prolactin may involve its initial interaction with fixed plasma membrane receptor sites. Subsequent actions of prolactin may involve the following: a) an increased intracellular concentration of potassium and a reduced level of sodium, b) an increased level of cGMP and a reduced level of cAMP, c) an enhanced rate of prostaglandin biosyntheesis mediated by a stimulation of phospholipase A2 activity, and d) a stimulation of polyamine synthesis. It has also been shown that the actions of prolactin require calcium ions in the extracellular environment. Laboratory studies have thus indicated that the actions of prolactin may be carried out by a number of processes; but a single, primary action of this hormone that accounts for all of its actions has not yet been proven.


Home-based infusion therapy for patients with Fabry disease.
Fabry disease is an inherited, progressive, life-threatening disease; therefore, lifelong therapy is needed. By replacing the deficient enzyme, disease progression may be delayed or halted, thereby avoiding serious complications. Hospital-based agalsidase therapy is generally perceived as inconvenient and home-based infusion therapy is greatly appreciated by patients, their families and healthcare professionals. Patients can get familiar with infusion therapy in a hospital setting and, if specific requirements are fulfilled, routine nurse-assisted infusion, or self-care, at the patient's home can be organized. A stable patient who tolerates the infusion and a suitable home environment are prerequisites for home therapy. The authors' clinical experiences underscore the safety and practicality of home therapy. In addition to a major positive impact on the patient's quality of life, home infusion therapy may reduce the constraints of hospital resources. This article reviews the collective experiences with agalsidase beta home infusion therapy and outlines how safe, patient-centred homecare can be organized. Home infusion therapy with Fabrazyme should not be withheld from patients considered eligible according to the proposed criteria. Similar approaches to other enzyme therapies are also possible.


Obstructive sleep apnea diagnosis and beyond using portable monitors.
Obstructive sleep apnea (OSA) is a chronic sleep and breathing disorder with significant health complications, including cardiovascular disease and neurocognitive impairments. To ensure timely treatment, there is a need for a portable, accurate and rapid method of diagnosing OSA. This review examines the use of various physiological signals used in the detection of respiratory events and evaluates their effectiveness in portable monitors (PM) relative to gold standard polysomnography. The primary objective is to explore the relationship between these physiological parameters and OSA, their application in calculating the apnea hypopnea index (AHI), the standard metric for OSA diagnosis, and the derivation of non-AHI metrics that offer additional diagnostic value. It is found that increasing the number of parameters in PMs does not necessarily improve OSA detection. Several factors can cause performance variations among different PMs, even if they extract similar signals. The review also highlights the potential of PMs to be used beyond OSA diagnosis. These devices possess parameters that can be utilized to obtain endotypic and other non-AHI metrics, enabling improved characterization of the disorder and personalized treatment strategies. Advancements in PM technology, coupled with thorough evaluation and validation of these devices, have the potential to revolutionize OSA diagnosis, personalized treatment, and ultimately improve health outcomes for patients with OSA. By identifying the key factors influencing performance and exploring the application of PMs beyond OSA diagnosis, this review aims to contribute to the ongoing development and utilization of portable, efficient, and effective diagnostic tools for OSA.


Mercury exposure of tidal marsh songbirds in the northeastern United States and its association with nest survival.
The biogeochemistry of tidal marsh sediments facilitates the transformation of mercury (Hg) into the biologically available form methylmercury (MeHg), resulting in elevated Hg exposures to tidal marsh wildlife. Saltmarsh and Acadian Nelson's sparrows (Ammospiza caudacutua and A. nelsoni subvirgatus, respectively) exclusively inhabit tidal marshes, potentially experiencing elevated risk to Hg exposure, and have experienced range-wide population declines. To characterize spatial and temporal variation of Hg exposure in these species, we sampled total mercury (THg) in blood collected from 9 populations spanning 560 km of coastline, including individuals resampled within and among years. Using concurrent nesting studies, we tested whether THg was correlated with nest survival probabilities, an index of fecundity. Blood THg ranged from 0.074-3.373 µg/g ww across 170 samples from 127 individuals. We detected high spatial variability in Hg exposure, observing differences of more than 45-fold across all individuals and 8-fold in mean blood THg among all study plots, including 4-fold between study plots within 4 km. Intraindividual changes in blood Hg exposure did not vary systematically in time but were considerable, varying by up to 2-fold within and among years. Controlling for both species differences and maximum water level, the dominant driver of fecundity in this system, nest survival probability decreased by 10% across the full range of female blood THg concentrations observed. We conclude that Hg has the potential to impair songbird reproduction, potentially exacerbating known climate-change driven population declines from sea-level rise in saltmarsh and Acadian Nelson's sparrows.


Influence of wheelchair user interface and personal characteristics on static and dynamic pretibial skin pressures in elite wheelchair racers, a pilot study.
Context/objective: To examine personal (athletic classification, age, sex, body mass index, duration of disability, tactile sensation of lower extremities) and wheelchair (kneeling plate angle) factors associated with increased pretibial skin pressures in elite wheelchair racers. Design: Cross-sectional study. Setting: University-based laboratory in Champaign, USA. Participants: A convenience sample of elite wheelchair races with traumatic spinal cord injury and spinal disease were recruited for participation. Interventions: Interface pressure mapping was used to examine athletes' average and peak pretibial skin pressures in their own racing wheelchairs during static and dynamic (propulsive) conditions on a dynamometer. Outcome measures: The study examined associations between personal and wheelchair factors and pressure, differences in pressure between static and dynamic conditions, and the influence of athletic classification (T53 vs. T54) on kneeling plate angle preference and skin pressure magnitudes. Results: Increased kneeling plate angle was moderately associated with dynamic pressures. T53 athletes utilized more vertical kneeling angles and experienced larger average and peak pressures during propulsion. Duration of disability was negatively associated with all measures of pressure. Overall, mean dynamic peak pressure was significantly greater than mean static peak pressure. Conclusion: This pilot study represents a first step in understanding the influence of user interface on potentially injurious skin pressures in wheelchair racers. Vertical kneeling plate configurations were associated with increased pressures while increased years with disability was associated with lower pretibial pressures. In addition, T53 athletes with less trunk function may be at a greater risk for experiencing larger interface pressures than T54 athletes.


Absence of pharyngeal shedding of vaccinia following smallpox vaccination.
To examine oral shedding of vaccinia in volunteers who were recently vaccinated against smallpox, pharyngeal swabs were collected for viral culture between days 3 and 5 and days 6 and 8 after vaccination with diluted Sanofi Pasteur smallpox vaccine. From 102 adult volunteers (48 vaccinia-naive, 54 vaccinia-experienced), vaccinia was not detected in any specimen (0/201, 95% confidence interval, 0-1.8), which suggests a lack of oral shedding of vaccinia after immunization. This supports recommendations that individuals who were recently vaccinated against smallpox do not require placement in airborne or droplet precautions.


Female reproductive success and calf survival in a North Sea coastal bottlenose dolphin (Tursiops truncatus) population.
Between-female variation in reproductive output provides a strong measure of individual fitness and a quantifiable measure of the health of a population which may be highly informative to management. In the present study, we examined reproductive traits in female bottlenose dolphins from the east coast of Scotland using longitudinal sightings data collected over twenty years. From a total of 102 females identified between 1997 and 2016, 74 mothers produced a collective total of 193 calves. Females gave birth from 6 to 13 years of age with a mean age of 8. Calves were produced during all study months, May to October inclusive, but showed a seasonal birth pulse corresponding to the regional peak in summer water temperatures. Approximately 83% (n = 116) of the calves of established fate were successfully raised to year 2-3. Of the known mortalities, ~45% were first-born calves. Calf survival rates were also lower in multiparous females who had previously lost calves. A mean inter-birth interval (IBI) of 3.80 years (n = 110) and mean fecundity of 0.16 was estimated for the population. Calf loss resulted in shortened IBIs, whilst longer IBIs were observed in females assumed to be approaching reproductive senescence. Maternal age and size, breeding experience, dominance, individual associations, group size and other social factors, were all concluded to influence reproductive success (RS) in this population. Some females are likely more important than others for the future viability of the population. Consequently, a better knowledge of the demographic groups containing those females showing higher reproductive success would be highly desirable for conservation efforts aimed at their protection.


Massive stars in their death throes.
The study of the stars that explode as supernovae used to be a forensic study, working backwards from the remnants of the star. This changed in 1987 when the first progenitor star was identified in pre-explosion images. Currently, there are eight detected progenitors with another 21 non-detections, for which only a limit on the pre-explosion luminosity can be placed. This new avenue of supernova research has led to many interesting conclusions, most importantly that the progenitors of the most common supernovae, type IIP, are red supergiants, as theory has long predicted. However, no progenitors have been detected thus far for the hydrogen-free type Ib/c supernovae, which, given the expected progenitors, is an unlikely result. Also, observations have begun to show evidence that luminous blue variables, which are among the most massive stars, may directly explode as supernovae. These results contradict the current stellar evolution theory. This suggests that we may need to update our understanding.


The 2001 epidemic of foot-and-mouth disease in the United Kingdom: epidemiological and meteorological case studies.
The possibility of the airborne spread of foot-and-mouth disease during the 2001 epidemic in the uk has been investigated in three epidemiological case studies. On the basis of evidence from field investigations, and a simple meteorological analysis, it is concluded that the spread of disease was consistent with the airborne transport of virus. The distances ranged from less than 1 km to 16 km; six of the farms were over 6 km from the source and involved the passage of virus over the sea combined with meteorological conditions which strongly favoured airborne disease transmission. The results of detailed atmospheric modelling demonstrated that airborne virus could have challenged livestock on all the farms studied. However, with one exception the 24-hour average daily concentrations of the virus were significantly below the experimentally estimated threshold for infection. A detailed model intercomparison established that, under stable atmospheric conditions, peak concentrations of virus up to two orders of magnitude higher might have been experienced for short periods, owing to fluctuations within the plume of virus, and model limitations. This finding would significantly reduce the apparent discrepancy between the experimentally estimated threshold for infection and the modelling results.


Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals.
To examine fat biopsy samples from lean insulin-sensitive and obese insulin-resistant nondiabetic individuals for evidence of endoplasmic reticulum (ER) stress. Subcutaneous fat biopsies were obtained from the upper thighs of six lean and six obese nondiabetic subjects. Fat homogenates were used for proteomic (two-dimensional gel and MALDI-TOF/TOF), Western blot, and RT-PCR analysis. Proteomic analysis revealed 19 differentially upregulated proteins in fat of obese subjects. Three of these proteins were the ER stress-related unfolded protein response (UPR) proteins calreticulin, protein disulfide-isomerase A3, and glutathione-S-transferase P. Western blotting revealed upregulation of several other UPR stress-related proteins, including calnexin, a membrane-bound chaperone, and phospho c-jun NH(2)-terminal kinase (JNK)-1, a downstream effector protein of ER stress. RT-PCR analysis revealed upregulation of the spliced form of X-box binding protein-1s, a potent transcription factor and part of the proximal ER stress sensor inositol-requiring enzyme-1 pathway. These findings represent the first demonstration of UPR activation in subcutaneous adipose tissue of obese human subjects. As JNK can inhibit insulin action and activate proinflammatory pathways, ER stress activation of JNK may be a link between obesity, insulin resistance, and inflammation.


Comparative study of two silicone hydrogel contact lenses used as bandage contact lenses after LASEK.
To evaluate two silicone hydrogel contact lens materials as continuous-wear bandage contact lenses after laser-assisted subepithelial keratomileusis (LASEK). The inclusion criteria were myopia of -6.00 diopters (D) or less, astigmatism lower than -1.5 D, bilateral best-corrected visual acuity of 20/20 or better, and candidates for bilateral LASEK. The patients were randomized to be fitted with a Balafilcon A (PureVision) lens in one eye and Galyfilcon A (Acuvue Advance) in the fellow eye. Uncorrected visual acuity, corneal epithelial status, conjunctival and limbal hyperemia, lens movement, contact lens debris, and the responses to a subjective-comfort questionnaire were assessed postoperatively. The parameters were evaluated before and 1 and 5 days after the procedure. A paired Student's t-test and chi-square tests were used when appropriate. We analyzed 44 eyes of 22 consecutive patients who underwent LASEK to correct low-to-moderate myopia. The mean spherical equivalent was -3.25 +/- 2.36 D. There was no difference in conjunctival or limbal hyperemia, lens movement, uncorrected visual acuity, or epithelial healing between the two lenses at any visit. A significant difference was found in lens deposition and discomfort, which were greater with the PureVision lens 5 days postoperatively (p = 0.01 for both comparisons). PureVision and Acuvue Advance contact lenses seem to be useful as continuous wear bandage contact lenses. There is no major clinical difference between the lenses, although patients report greater comfort with Acuvue Advance.


Hyperemesis gravidarum: outcomes and complications with and without total parenteral nutrition.
To evaluate the obstetric and medical complications with hyperemesis gravidarum, comparing those who were supported with total parenteral nutrition (TPN group) and those who did not receive TPN (non-TPN group). The medical records of women with a diagnosis of hyperemesis gravidarum (ICD-9 code 643) admitted to Crouse Hospital, Syracuse, New York, between January 1995 and December 1998, were reviewed. A total of 166 subjects were identified and 192 admissions reviewed. Information was gathered for age, gestational age, gravity and parity, marital status, length of stay and number of admissions, and a review of electrolyte, albumin and thyroid function was performed. An assessment of pregnancy complications and outcomes was undertaken. Of the cases reviewed, 16% (27/166) were treated with TPN. The 2 groups were similar regarding incidence of pregnancy-related and maternal medical complications. The groups were similar when comparing objective measures, such as serum potassium, bicarbonate, albumin and thyroid function. The TPN group had a significantly increased incidence of complications directly attributable to parenteral therapy. Among multiparous patients in both groups, 69% had a prior pregnancy that had ended in spontaneous or induced abortion. The TPN group had a marked and significant increase in serious complications directly related to TPN use. These data suggest that great care should be taken to assess the need for parenteral therapy in patients with hyperemesis gravidarum. A history of loss in the antecedent pregnancy may be a risk factor for a subsequent pregnancy complicated by hyperemesis gravidarum.


Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma.
A first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2+ patients with advanced melanoma. Patient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins. Sixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8+ T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis. Combined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents. NCT01876212.


Villoglandular Papillary Adenocarcinoma With Cervical Intraepithelial Neoplasia 3 of the Cervix in a Woman With a Misdiagnosis of a Cervical Polyp.
We report a case in which a polypoid lesion with a diameter of 5 mm was diagnosed as a cervical polyp due to a negative Papanicolaou (Pap) smear in the cervix, and polypectomy revealed a diagnosis of villoglandular papillary adenocarcinoma (VGA) on histopathological examination. A 63-year-old woman with a cervical polyp, who had no abnormal symptoms and a negative Pap smear was referred to our hospital. We performed cervical polypectomy, and the pathological result was VGA with cervical intraepithelial neoplasia (CIN) 3. Even if an asymptomatic cervical polyp with a negative Pap smear is diagnosed, in some patients VGA of the uterine cervix may coexist with CIN. Therefore, asymptomatic cervical polyps with negative Pap smears should not be followed up without removal.


A simple approach to assess N load capacity of rice paddy fields in the southern Taihu Lake watershed.
High nitrogen (N) leaching from irrigated agricultural soils is the result of N input exceeding soil N load capacity (NLC). A simple approach was developed in this research to assess the NLC of paddy soils in the southern Taihu Lake watershed. Paddy soils were classified into four types (Submergenic, Illuvium, Gleyed, and Percogenic) and 28 soil samples representing all four types were collected from across the region. The NLC values of the paddy soils were assessed using a split-line model and the spatial variability of the NLC among various rice paddy soils in the region was also evaluated with Kriging analysis. Results showed the NLC of paddy soils were both soil type and background N content related. The critical N sorption values (NLC plus soil N background) of the Gleyed, Illuvium, Submergenic, and Percogenic paddy soil samples varied from 283.1 to 315.6 mg kg(-1), 203.0 to 270.2 mg kg(-1), 240.6 to 254.4 mg kg(-1), and 177.4 to 186.2 mg kg(-1), respectively. However, on average the NLC of paddy soils in the region was 80.3 mg kg(-1), and the corresponding environmental N load threshold was around 110 kg N ha(-1). Geo-statistic results showed that the NLCs were unevenly distributed throughout the rice paddy dominated areas of the southern Taihu Lake watershed. The NLC assessment approach and spatial distribution information provided helpful guidance to set an environmental N threshold for best N management and hence reduce degradation of water for the whole rice ecosystem.


Bayesian wavelet-based image deconvolution: a GEM algorithm exploiting a class of heavy-tailed priors.
Image deconvolution is formulated in the wavelet domain under the Bayesian framework. The well-known sparsity of the wavelet coefficients of real-world images is modeled by heavy-tailed priors belonging to the Gaussian scale mixture (GSM) class; i.e., priors given by a linear (finite of infinite) combination of Gaussian densities. This class includes, among others, the generalized Gaussian, the Jeffreys, and the Gaussian mixture priors. Necessary and sufficient conditions are stated under which the prior induced by a thresholding/shrinking denoising rule is a GSM. This result is then used to show that the prior induced by the "nonnegative garrote" thresholding/shrinking rule, herein termed the garrote prior, is a GSM. To compute the maximum a posteriori estimate, we propose a new generalized expectation maximization (GEM) algorithm, where the missing variables are the scale factors of the GSM densities. The maximization step of the underlying expectation maximization algorithm is replaced with a linear stationary second-order iterative method. The result is a GEM algorithm of O(N log N) computational complexity. In a series of benchmark tests, the proposed approach outperforms or performs similarly to state-of-the art methods, demanding comparable (in some cases, much less) computational complexity.


Genomic relationships between Dasypyrum villosum (L.) Candargy and D. hordeaceum (Cosson et Durieu) Candargy.
The origin and genomic constitution of the tetraploid perennial species Dasypyrum hordeaceum (2n = 4x = 28) and its phylogenetic relationships with the annual diploid Dasypyrum villosum (2n = 2x = 14) have been investigated by comparing the two genomes using different methods. There is no apparent homology between the conventional or Giemsa C-banded karyotypes of the two Dasypyrum species, nor can the karyotype of D. hordeaceum be split up into two similar sets. Polymorphism within several chromosome pairs was observed in both karyotypes. Cytophotometric determinations of the Feulgen-DNA absorptions showed that the genome size of D. hordeaceum was twice as large as that of D. villosum. Both the cross D. villosum x D. hordeaceum (crossability rate 12.1%) and the reciprocal cross (crossability rate 50.7%) produced plump seeds. Only those from the former cross germinated, producing sterile plants with a phenotype that was intermediate between those of the parents. In these hybrids (2n = 21), an average of 13.77 chromosomes per cell paired at meiotic metaphase I. Trivalents were only rarely observed. Through dot-blot hybridizations, a highly repeated DNA sequence of D. villosum was found not to be represented in the genome of D. hordeaceum. By contrast, very similar restriction patterns were observed when a low-repeated DNA sequence or different single-copy sequences of D. villosum or two sequences in the plastidial DNA of rice were hybridized to Southern blots of the genomic DNAs of the two Dasypyrum species digested with different restriction endonucleases. By analyzing glutamic-oxaloacetic-transaminase, superoxide dismutase, alcohol dehydrogenase, and esterase isozyme systems, it was shown that both Dasypyrum species shared the same phenotypes, which differed from those found in hexaploid wheat. In situ hybridizations using DNA sequences encoding gliadins showed that these genes were located close to the centromere of three pairs of D. villosum chromosomes and that they had the same locations in six pairs of D. hordeaceum chromosomes. We conclude that the autoploid origin of D. hordeaceum from D. villosum, which cannot be defended on the basis of chromosomal traits, is suggested by the other findings obtained by comparing the two genomes. Key words : Dasypyrum hordeaceum, Dasypyrum villosum, phylogenetic relationships.


Assaying for BRAF V600E in tissue and blood in melanoma.
The Braf(V600E) mutation has been detected in patients with metastatic melanoma, colon, thyroid, and other cancers. Studies suggested that tumors with this mutation are especially sensitive to BRAF inhibitors-hence the need to reliably determine the BRAF status of tumor specimens. The present technologies used to screen for this mutation fail to address the problems associated with infiltrating stromal and immune cells bearing wild-type BRAF alleles and thus may fail to detect the presence of mutant BRAF(V600E) tumors. We have developed a rapid, inexpensive method of BRAF analysis that reduces the contamination of wild-type BRAF sequences from tumor biopsies. The protocol involves a series of PCR amplifications and restriction digestions that take advantage of unique features of both wild-type and mutant BRAF RNA at codon 600. Using this protocol, mutant BRAF can be detected in RNA from mixed populations with as few as 0.1 % BRAF(V600E) mutant containing cells.


Bifurcating effects of hope and support in short- and long-term health outcomes among primary care patients without mental illness.
Adverse life events and stressors can lead to symptoms, increased alcohol intake, and impaired functional status, while hope and social support can mitigate such adverse effects. Yet, there is reason to question such simple, linear relationships among healthy adults. The purpose of this study was to assess whether short-term or long-term changes in alcohol intake, psychological symptoms or functional status were better modelled as cusp catastrophic or linear processes among primary care patients without mental illness. This secondary analysis of a study on the stability of psychological symptoms among primary care patients without mental disorders included 38 subjects who completed baseline, and 2-month and/or 6-month assessments of psychological symptoms, functional status and stressors as well as hope and social support. The analyses modelled short-term and long-term changes in alcohol intake, psychological symptoms and functional status using cusp catastrophe (CCM) and linear modelling. Overall, four of the nine 2-month analyses found CCM superior to linear models; however, only one 6-month analysis (alcohol intake) found that CCM was superior. The 2-month cusp phenomena included both symptomatology and functional status. The asymmetry variables were often not significant in the CCM models; in fact, only distress was significant at all. While hope was a significant bifurcation variable at both the 2-month and 6-month levels, social support was a significant bifurcation variable for three of the four 2-month CCMs. In conclusion, while 6-month outcomes were rarely explained through CCM, half of 2-month outcomes were. Hope and support demonstrated bifurcation effects.


Evaluation of Gamma Amino Butyric Acid (GABA) and Glibenclamide Combination Therapy in Streptozotocin Induced Diabetes.
Type 1-diabetes (T1D) is characterized by autoimmune destruction of β-cells and loss of endogenous insulin. A lifelong dependency on exogenous supply of insulin presents a great challenge in the pharmacotherapy of T1D that elicits a quest for alternative therapies, which can protect β-cells and revive their insulinogenic functions. GABA (γ-aminobutyric acid) has immunoprotective and β-cell regenerative capabilities. Co-administration of an insulin secretagogue, such as glibenclamide (Glib), along with GABA may enhance the pancreatic insulin output in T1D. The present study evaluated the possible mechanism of GABA in the improvement of glucose tolerance and its effects in streptozotocin (STZ) induced T1D along with Glib. Wistar rats (180-220 g) were administered a single dose of STZ (55 mg/kg, i.p.). GABA (100 mg/kg, i.p.) and Glib (5 or 10 mg/kg, i.p.) alone or in combination were administered for 28 days. Body weight (b.w.), water consumption, fasting blood glucose (FBG), oral glucose tolerance, plasma lipids, insulin, and muscle GLUT-4 (glucose transporters) protein level were assessed. T1D significantly decreased b.w. and increased water-intake in rats. An increase in FBG and a decrease in plasma insulin and muscle GLUT-4 indicated STZ-triggered destruction of β-cells in diabetic rats accompanied with dyslipidemia. GABA or Glib (10 mg/kg) significantly improved b.w., plasma insulin and GLUT-4 levels, and ameliorated FBG and blood lipid profile in diabetic rats. GABA and Glib (5 mg/kg) combination therapy achieved far better control over hyperglycemia and related pathogenic conditions (b.w., water-intake, insulin, GLUT-4, lipids). The anti-diabetic effect of combination therapy was significantly more pronounced in comparison to individual drug treatments. Histopathological analysis revealed an increase in the number of functional pancreatic-islets by combination therapy. GABA revitalized β-cells against STZ-toxicity. GABA and Glib synergistically augmented insulin secretion that can be used to manage T1D and its complications. GABA has the potential to remarkably enhance the therapeutic outcome in diabetic patients and reduce the dose of existing anti-diabetic drugs such as Glib.


Fluorophosphonate-functionalised titanium via a pre-adsorbed alkane phosphonic acid: a novel dual action surface finish for bone regenerative applications.
Enhancing vitamin D-induced human osteoblast (hOB) maturation at bone biomaterial surfaces is likely to improve prosthesis integration with resultant reductions in the need for revision arthroplasty consequent to aseptic loosening. Biomaterials that are less appealing to microorganisms implicated in implant failures through infection are also highly desirable. However, finding surfaces that enhance hOB maturation to active vitamin D yet deter bacteria remain elusive. In addressing this, we have sought to bio-functionalise titanium (Ti) with lysophosphatidic acid (LPA) and related, phosphatase-resistant, LPA analogues. The impetus for this follows our discovery that LPA co-operates with active vitamin D3 metabolites to secure hOB maturation in vitro including cells grown upon Ti. LPA has also been found, by others, to inhibit virulence factor production and biofilm formation of the human opportunistic pathogen Pseudomonas aeruginosa. Collectively, selected LPA species might offer potential dual-action surface finishes for contemporary bone biomaterials. In attaching a phosphatase-resistant LPA analogue to Ti we took advantage of the affinity of alkane phosphonic acids for TiO2. Herein, we provide evidence for the facile development of a dual-action Ti surface for potential orthopaedic and dental applications. Successful conjugation of an LPA analogue (3S)1-fluoro-3-hydroxy-4-(oleoyloxy)butyl-1-phosphonate (FHBP) to the Ti surface was supported through physiochemical characterisation using x-ray photoelectron spectroscopy and secondary ion mass spectrometry. hOB maturation to active vitamin D3 was enhanced for cells grown on FHBP-Ti whilst these same surfaces exhibited clear antiadherent properties towards a clinical isolate of Staphylococcus aureus.


What is the evidence to support acetabular dysplasia as a cause of osteoarthritis?
The term "acetabular dysplasia" suggests a smaller than normal acetabulum or one that is abnormally vertical. Acetabular dysplasia has been linked to the development of hip osteoarthritis over the last 90 years in 3 ways. First, it has been linked through the concept that biomechanical forces can cause osteoarthritis. A smaller than normal acetabulum will result in a smaller than normal contact surface between the femoral head and the acetabulum. This will generate increased pressure per unit of area, which will precipitate articular cartilage failure when the pressure reaches a critical point. Osteoarthritis will ensue in response to this cartilage failure. A more vertical than normal acetabulum will be associated with increased shear. When that shear reaches a critical level, articular cartilage will fail, leading that to osteoarthritis. This critical level, for a small or a steep acetabulum, may differ between individuals, based on their biology and their life styles. Second, it has been linked by multiple empirical studies. One of these is Wiberg's 1939 thesis entitled "Studies on Dysplastic Acetabula and Congenital Subluxation of the Hip Joint with Special reference to the Complication of Osteoarthritis." It is among the most quoted and most powerful works in the Orthopaedic literature connecting a disease entity with an antecedent. Third, the linkage is reenforced by an absence of glaring exceptions to the hypothesis that acetabular dysplasia causes osteoarthritis. Orthopaedic surgeons just do not report on dysplastic hips in the arthritis-free elderly. The inability of the Orthopaedic community to identify even 1 elderly, arthritis-free individual with significant hip dysplasia should not carry weight in establishing the concept that acetabular dysplasia causes osteoarthritis. However, the longer this case report goes unpublished, the more certain orthopaedic surgeons will be that the 2 are linked.


Hybridization between Crocodylus acutus and Crocodylus moreletii in the Yucatan Peninsula: II. Evidence from microsatellites.
Detecting and quantifying hybridization between endangered or threatened taxa can provide valuable information with regards to conservation and management strategies. Hybridization between members of the genus Crocodylus has been known to occur in captivity and in some wild populations. We tested for hybridization among wild populations of American crocodile (C. acutus) and Morelet's crocodile (C. moreletii) in the Yucatan Peninsula by comparing Bayesian assignment tests, based on microsatellite data, to mitochondrial and morphological assignments. Skin clips from 83 individuals were taken for genetic identification, and a total of 32 individuals (38.6%) exhibited some evidence of hybridization by combined morphological, mitochondrial and microsatellite analyses. The majority of hybrids were classified as F(2) hybrids and backcrosses to C. moreletii. Most of the introgression occurs in two national biosphere reserves located on the northern and eastern coasts of the Yucatan Peninsula. Preliminary tests did not find a significant decrease in hybridity across three life stages, thus far indicating a low level of selection against hybrids. Model-based analyses on multilocus genotypes of pure individuals returned little geographic partitioning in both C. acutus and C. moreletii.


Serum regucalcin is a useful indicator of liver injury severity in patients with hepatitis B virus-related liver diseases.
Regucalcin is a soluble protein that is principally expressed in hepatocytes. Studies of regucalcin have mainly been conducted in animals due to a lack of commercially available kits. We aimed to develop an enzyme-linked immunosorbent assay (ELISA) to quantify serum regucalcin in patients with hepatitis B virus (HBV)-related disease. High-titer monoclonal antibodies and a polyclonal antibody to regucalcin were produced, a double-antibody sandwich ELISA method was established, and serum regucalcin was determined in 47 chronic hepatitis B (CHB) patients, 91 HBV-related acute-on-chronic liver failure (HBV-ACLF) patients, and 33 healthy controls. The ELISA demonstrated an appropriate linear range, and high levels of reproducibility, sensitivity, specificity, accuracy, and stability. The median serum regucalcin concentrations in HBV-ACLF and CHB patients were 5.46 and 3.76 ng/mL, respectively (P<0.01), which were much higher than in healthy controls (1.72 ng/mL, both P<0.01). For the differentiation of CHB patients and healthy controls, the area under curve (AUC) was 0.86 with a cut-off of 2.42 ng/mL, 85.7% sensitivity, and 78.8% specificity. In contrast, the AUC of alanine aminotransferase (ALT) was lower (AUC=0.80, P=0.01). To differentiate ACLF from CHB, the AUC was 0.72 with a cut-off of 4.26 ng/mL, 77.0% sensitivity, and 61.2% specificity while the AUC of ALT was 0.41 (P=0.07). Thus, we have developed an ELISA that is suitable for measuring serum regucalcin and have shown that serum regucalcin increased with the severity of liver injury due to HBV-related diseases, such that it appears to be more useful than ALT as a marker of liver injury.


A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumor syndrome.
Familial primary hyperparathyroidism is the main feature of 2 familial endocrine neoplasia syndromes: multiple endocrine neoplasia type 1 (MEN 1) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The latter is a recently described syndrome that has been associated with ossifying fibroma of the jaw and various types of renal lesions, including benign cysts, Wilms' tumor, and hamartomas. To further illustrate the natural history of this syndrome, we describe a large, previously unreported Dutch kindred in which 13 affected members presented with either parathyroid adenoma or carcinoma; in 5 affected individuals, cystic kidney disease was found. Additionally, pancreatic adenocarcinoma, renal cortical adenoma, papillary renal cell carcinoma, testicular mixed germ cell tumor with major seminoma component, and Hürthle cell thyroid adenoma were also identified. Linkage analysis of the family using MEN1-linked microsatellite markers and mutation analysis excluded the involvement of the MEN1 gene. Using markers from the HPT-JT region in 1q2531, cosegregation with the disease was found, with a maximum logarithm of odds score of 2.41 obtained for 6 markers using the most conservative calculation. Meiotic telomeric recombination between D1S413 and D1S477 was identified in 3 affected individuals, and when combined with previous reports, delineated the HPT-JT region to 14 centimorgan. Combined comparative genomic hybridization and loss of heterozygosity data revealed complex genetic abnormalities in the tumors, suggesting different possible genetic mechanisms for the disease. In conclusion, we report a family with hyperparathyroidism linked to chromosome 1q, and exhibiting several types of renal and endocrine tumors that have not been previously described.


Review of abnormal laboratory test results and toxic effects due to use of herbal medicines.
Herbal medicines are used widely in the United States, and according to a recent survey, the majority of people who use herbal medicines do not inform their physicians about their use. Herbal medicines can cause abnormal test results and confusion in proper diagnosis. Herbal medicines can alter test results by direct interference with certain immunoassays. Drugherb interactions can result in unexpected concentrations of therapeutic drugs. For example, low concentrations of several drugs (e.g., cyclosporine, theophylline, digoxin) can be observed in patients who initiated self-medication with St John's wort. Herbal medicines can alter physiology, and these changes can be reflected in abnormal test results. For example, kavakava can cause drug-induced hepatitis, leading to unexpected high concentrations of liver enzymes. Use of toxic herbal products such as ma huang (an ephedra-containing herbal product), Chan Su, and comfrey may cause death. Other toxic effects of herbal medicines include cardiovascular toxic effects, hematologic toxic effects, neurotoxic effects, nephrotoxic effects, carcinogenic effects, and allergic reactions.


A modified method of genomic DNA preparation in agarose inserts for pulse field gel electrophoresis.
According to standard protocol, DNA in agarose inserts is prepared by first embedding the cell in agarose. This is then incubated in the required enzyme (lysozyme, lysostaphin, or zymolase) depending on the cell type (bacterial or plants), for spheroplast formation. Subsequent treatment of the spheroplast with proteinase K allows the isolation of large genomic DNA in agarose suitable for pulse field gel electrophoresis. An efficient and rapid method of preparation of spheroplast is described. In this method a low concentration of enzyme required for spheroplast formation was added before embedding the cell in agarose, which facilitated the digestion of cell wall by the enzyme and allowed use of a low amount of enzyme. Digestion of DNA in agarose inserts prepared by this method, with rare cutting restriction enzyme and pulse field gel electrophoresis, showed that the quality of DNA was as good as obtained by the standard method.


Lower nicotine cigarettes may not lower harm.
In 2005, nearly 21% of American adults smoked cigarettes, and 81% of them smoked every day. For smokers unable or unwilling to quit, tobacco products that reduce the adverse health effects of smoking may be an attractive option. Potentially reduced exposure products (PREPs) were developed by the tobacco industry in response to smokers' health concerns. PREPs purportedly lower the tar and/or nicotine levels of cigarettes, although the actual harm reduced remains questionable. One of the most recent additions to this product class are cigarettes that use genetically modified tobacco to reduce nicotine levels. This Issue Brief summarizes studies that investigate [1] how this product is used and [2] the messages smokers take away from product marketing. These complementary studies send a cautionary signal about the ability of these new cigarettes to reduce the harmful effects of smoking.


Field-based remote sensing models predict radiation use efficiency in wheat.
Wheat yields are stagnating or declining in many regions, requiring efforts to improve the light conversion efficiency, known as radiation use efficiency (RUE). RUE is a key trait in plant physiology because it links light capture and primary metabolism with biomass accumulation and yield, but its measurement is time consuming and this has limited its use in fundamental research and large-scale physiological breeding. In this study, high-throughput plant phenotyping (HTPP) approaches were used among a population of field-grown wheat with variation in RUE and photosynthetic traits to build predictive models of RUE, biomass, and intercepted photosynthetically active radiation (IPAR). Three approaches were used: best combination of sensors; canopy vegetation indices; and partial least squares regression. The use of remote sensing models predicted RUE with up to 70% accuracy compared with ground truth data. Water indices and canopy greenness indices [normalized difference vegetation index (NDVI), enhanced vegetation index (EVI)] are the better option to predict RUE, biomass, and IPAR, and indices related to gas exchange, non-photochemical quenching [photochemical reflectance index (PRI)] and senescence [structural-insensitive pigment index (SIPI)] are better predictors for these traits at the vegetative and grain-filling stages, respectively. These models will be instrumental to explain canopy processes, improve crop growth and yield modelling, and potentially be used to predict RUE in different crops or ecosystems.


Are we training our residents to perform open gall bladder and common bile duct operations?
In the new era of resident work hour restrictions and an emphasis on minimally invasive surgery, experience in performing open biliary surgery is diminishing. We sought to review our resident operative experience to determine if it appears adequate for a well-trained general surgeon. The case logs of the General Surgery, Oncology, and Trauma/Emergency General Surgery (EGS) services were reviewed for a 1-year period. All biliary procedures that included the potential for gallbladder or bile duct surgery were reviewed. We performed 745 laparoscopic cholecystectomies last year on our General Surgery, Oncology, and Trauma/EGS services. Conversion to open procedure was 4.5% (16/364) on our elective services and 6% (23/381) on our Trauma/EGS services. Effective clearance of common bile duct stones performed retrograde by endoscopy and transhepatically by interventional radiology limited our residents' experience performing common bile duct surgery for stones to 13 performed laparoscopically and 10 performed open. Other operations that included open cholecystectomies and common bile duct procedures were pancreatico-duodenectomy (87), biliary bypass (22), biliary resection/reconstruction (20), hepatic lobectomy (48), sphincteroplasty and ampullectomy (6). The small number of conversions from laparoscopic to open cholecystectomies and the few common bile duct explorations performed for stone disease would be inadequate to train our six categorical surgical residents to perform open cholecystectomies and common bile duct procedures without a training program that augments this by providing a strong hepato-biliary-pancreatic experience. Programs without a strong hepato-biliary-pancreatic program should review their residents' operative experience.


Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation.
Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.


[Cardiac electrical device therapy in heart failure].
Heart failure is one of the most common reasons for inpatient treatment and one of the most common causes of death in Germany. In addition to coronary heart disease (ischemic cardiomyopathy, ICM), there are also numerous other diseases as non-ischemic cardiomyopathy, NICM. Chronic heart failure is the final stage of diseases with cardiac involvement and limits the prognosis and quality of life of patients. The course can be favorably influenced by cardiac implantable electrical devices (CIEDs). There are different uses of CIEDs which are shown in this article.


Helical tomotherapy as a means of delivering accelerated partial breast irradiation.
A novel treatment approach utilizing helical tomotherapy for partial breast irradiation for patients with early-stage breast cancer is described. This technique may serve as an alternative to high dose-rate (HDR) interstitial brachytherapy and standard linac-based approaches. Through helical tomotherapy, highly conformal irradiation of target volumes and avoidance of normal sensitive structures can be achieved. Unlike HDR brachytherapy, it is noninvasive. Unlike other linac-based techniques, it provides image-guided adaptive radiotherapy along with intensity modulation. A treatment planning CT scan was obtained as usual on a post-lumpectomy patient undergoing HDR interstitial breast brachytherapy. The patient underwent catheter placement for HDR treatment and was positioned prone on a specially designed position-supporting mattress during CT. The planning target volume (PTV) was defined as the lumpectomy bed plus a 20 mm margin. The prescription dose was 34 Gy (10 fx of 3.4 Gy) in both the CT based HDR and on the tomotherapy plan. Cumulative dose-volume histograms (DVHs) were generated and analyzed for the target, lung, heart, skin, pectoralis muscle, and chest wall for both HDR brachytherapy and helical tomotherapy. Dosimetric coverage of the target with helical tomotherapy was conformal and homogeneous. "Hot spots" (> or =150% isodose line) were present around implanted dwell positions in brachytherapy plan whereas no isodose lines higher than 109% were present in the helical tomotherapy plan. Similar dose coverage was achieved for lung, pectoralis muscle, heart, chest wall and breast skin with the two methods. We also compared our results to that obtained using conventional linac-based three dimensional (3D) conformal accelerated partial breast irradiation. Dose homogeneity is excellent with 3D conformal irradiation, and lung, heart and chest wall dose is less than for either HDR brachytherapy or helical tomotherapy but skin and pectoral muscle doses were higher than with the other techniques. Our results suggest that helical tomotherapy can serve as an effective means of delivering accelerated partial breast irradiation and may offer superior dose homogeneity compared to HDR brachytherapy.


5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma.
The technique of 5-aminolevulinic acid (5-ALA) tumor fluorescence is increasingly used to improve visualization of tumor tissue and thereby to increase the rate of patients with gross total resections. In this study, we measured the resection volumes in patients who underwent 5-ALA-guided surgery for non-eloquent glioblastoma and compared them with the preoperative tumor volume. We selected 13 patients who had received a complete resection according to intraoperative 5-ALA induced fluorescence and CRET according to post-operative T1 contrast-enhanced MRI. The volumes of pre-operative contrast enhancing tissue, post-operative resection cavity and resected tissue were determined through shift-corrected volumetric analysis. The mean resection cavity (29 cm(3)) was marginally smaller than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.32). However, the mean overall resection volume (84 cm(3)) was significantly larger than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.0087). This yields a mean volume of resected 5-ALA positive, but radiological non-enhancing tissue of 45 cm(3). The mean calculated rim of resected tissue surpassed pre-operative tumor diameter by 6 mm (range 0-10 mm). Results of the current study imply that (i) the resection cavity underestimates the volume of resected tissue and (ii) 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk.


Virological and immunological outcomes in HIV-1-infected Chinese patients treated with a combination of Efavirenz and Indinavir for 48 weeks.
The incidence of HIV-1-related infection diseases and the mortality of AIDS have dramatically decreased since highly active antiretroviral therapy began to be used clinically in China in 1999. And we initiated a second clinical trial using a combination of Efavirenz and Indinavir to observe the effects of the immunoreaction. Twenty patients with laboratory-confirmed chronic HIV-1 infection were recruited. Blood samples were collected initially and during the weeks after initiation of treatment. Within 48 hours of blood sampling, peripheral blood plasma and mononuclear cells were separated using routine methods. HIV-1 viral load was measured in thawed plasma samples. Within 48 hours of peripheral blood sampling, CD4(+) and CD8(+) T cell subsets were enumerated. The drug regimen was efficient in reducing HIV-1 plasma viral load and increasing total CD4(+) T cell counts. The percentage of CD4(+) and CD8(+) T cell subsets expressing CD38 and HLA-DR activation markers was positively correlated with plasma viral load and tended to normalize. The combination of Efavirenz and Indinavir was generally well tolerated and efficient at reducing HIV-1 RNA. Furthermore, the treatment improved the immunological function.


[Low-invasive surgery of diffuse peritonitis complicated by abdominal sepsis].
On the experience of treatment of 45 patients the efficacy of the programmed control sanation laparoscopy of the abdominal cavity was proved in postoperative period. This method had an advantage in comparison with open approach. Postoperative complications decreased from 50% to 28.8% (p < 0.05), the length of hospital stay and fatal outcomes reduced from 15.1% to 11.1% (p < 0.05). It was established by cardiointervalography, that laparoscopic methods of sanation reduced the degree of trauma during the intervention and prevented the adaptation mechanisms from tension and suppression of reserve compensatory possibilities of patient's organism.


An anchor site-type defect in human telomerase that disrupts telomere length maintenance and cellular immortalization.
Telomerase-mediated telomeric DNA synthesis is important for eukaryotic cell immortality. Telomerase adds tracts of short telomeric repeats to DNA substrates using a unique repeat addition form of processivity. It has been proposed that repeat addition processivity is partly regulated by a telomerase reverse transcriptase (TERT)-dependent anchor site; however, anchor site-mediating residues have not been identified in any TERT. We report the characterization of an N-terminal human TERT (hTERT) RNA interaction domain 1 (RID1) mutation that caused telomerase activity defects consistent with disruption of a template-proximal anchor site, including reduced processivity on short telomeric primers and reduced activity on substrates with nontelomeric 5' sequences, but not on primers with nontelomeric G-rich 5' sequences. This mutation was located within a subregion of RID1 previously implicated in biological telomerase functions unrelated to catalytic activity (N-DAT domain). Other N-DAT and C-terminal DAT (C-DAT) mutants and a C-terminally tagged hTERT-HA variant were defective in elongating short telomeric primers, and catalytic phenotypes of DAT variants were partially or completely rescued by increasing concentrations of DNA primers. These observations imply that RID1 and the hTERT C terminus contribute to telomerase's affinity for its substrate, and that RID1 may form part of the human telomerase anchor site.


Recent Advancements in Drug Delivery of Sinomenine, A Disease-Modifying Anti-Rheumatic Drug.
Sinomenine (SIN) is a benzyltetrahydroisoquinoline-type alkaloid isolated from the dried plant root and stem of Sinomenium acutum (Thumb.) Rehd.et Wils, which shows potent anti-inflammatory and analgesic effects. As a transforming disease-modifying anti-rheumatic drug, SIN has been used to treat rheumatoid arthritis over twenty-five years in China. In recent years, SIN is also in development for use against other disorders, including colitis, pain, traumatic brain injury, and uveitis. However, its commercial hydrochloride (SIN-HCl) shows low oral bioavailability and certain allergic reactions in patients, due to the release of histamine. Therefore, a large number of pharmaceutical strategies have been explored to address these liabilities, such as prolonging release behaviors, enhancing skin permeation and adsorption for transdermal delivery, targeted SIN delivery using new material or conjugates, and co-amorphous technology. This review discusses these different delivery strategies and approaches employed to overcome the limitations of SIN for its efficient delivery, in order to achieve improved bioavailability and reduced side effects. The potential advantages and limitations of SIN delivery strategies are elaborated along with discussions of potential future SIN drug development strategies.