Platonin protects against cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasomes via BNIP3/LC3 signaling mediated autophagy.
Studies have found that Platonin has neuroprotective effect, but its molecular mechanism needs further study. We found that at the early stage of cerebral ischemia/reperfusion injury, Platonin treatment significantly reduced cerebral infarct lesions, improved neurological scores, and exerted neuroprotective effects. Our group has shown that NLRP3 inflammasomes activation is required to mediate neuronal injury during cerebral ischemia /reperfusion injury. The brain protective effect of Platonin is related to its ability to effectively regulate autophagy and NLRP3 inflammasomes-derived inflammation. Platonin treatment effectively induced autophagy (LC3II/I, p62) and reduced NLRP3 inflammasomes activation(NLRP3, cleaved-IL-1β,cleaved-IL-18, cleaved-caspase1). However, 3-MA (15 mg/kg) treatment downregulated the inhibitory effect of Platonin on NLRP3 inflammasomes. We also studied the location of BNIP3 in Platonin-mediated neuroprotection and found that Platonin induced the expression of autophagic protein BNIP3 and enhanced the co-immunoprecipitation of BNIP3 with LC3, and double-labeled immunofluorescence also showed enhanced co-localization of BNIP3 with LC3. Finally, si-BNIP3 transfection attenuated the co localization of BNIP3 with LC3, decreased the autophagy activity to a certain extent and blocked the inhibition of NLRP3 inflammasomes-derived inflammation by Platonin. This study demonstrated that Platonin may play a neuroprotection role in cerebral I / R injury by inhibiting NLRP3 inflammasomes activation through upregulating autophagy via BNIP3 / LC3 pathway.


ADORA2A variation and adenosine A1 receptor availability in the human brain with a focus on anxiety-related brain regions: modulation by ADORA1 variation.
Adenosine, its interacting A1 and A2A receptors, and particularly the variant rs5751876 in the A2A gene ADORA2A have been shown to modulate anxiety, arousal, and sleep. In a pilot positron emission tomography (PET) study in healthy male subjects, we suggested an effect of rs5751876 on in vivo brain A1 receptor (A1AR) availability. As female sex and adenosinergic/dopaminergic interaction partners might have an impact on this rs5751876 effect on A1AR availability, we aimed to (1) further investigate the pilot male-based findings in an independent, newly recruited cohort including women and (2) analyze potential modulation of this rs5751876 effect by additional adenosinergic/dopaminergic gene variation. Healthy volunteers (32/11 males/females) underwent phenotypic characterization including self-reported sleep and A1AR-specific quantitative PET. Rs5751876 and 31 gene variants of adenosine A1, A2A, A2B, and A3 receptors, adenosine deaminase, and dopamine D2 receptor were genotyped. Multivariate analysis revealed an rs5751876 effect on A1AR availability (P = 0.047), post hoc confirmed in 30 of 31 brain regions (false discovery rate (FDR) corrected P values < 0.05), but statistically stronger in anxiety-related regions (e.g., amygdala, hippocampus). Additional effects of ADORA1 rs1874142 were identified; under its influence rs5751876 and rs5751876 × sleep had strengthened effects on A1AR availability (Pboth < 0.02; post hoc FDR-corrected Ps < 0.05 for 29/30 regions, respectively). Our results support the relationship between rs5751876 and A1AR availability. Additional impact of rs1874142, together with rs5751876 and sleep, might be involved in regulating arousal and thus the development of mental disorders like anxiety disorders. The interplay of further detected suggestive ADORA2A × DRD2 interaction, however, necessitates larger future samples more comparable to magnetic resonance imaging (MRI)-based samples.


Updated strategies in the treatment of benign diseases-a patterns of care study of the german cooperative group on benign diseases.
Radiation therapy (RT) is a common treatment for benign diseases in Germany. Because the treatment concepts are inconsistent, we conducted this pattern-of-care study on behalf of the German Cooperative Group on Benign Diseases to evaluate treatment standards in Germany. Questionnaires were mailed to all radiation therapy facilities in Germany. We assessed the treatment equipment, annual number of patients, treatment indications, and, in particular, treatment strategies in patients with benign diseases in 2014. We evaluated questionnaires returned by 116 participating institutions, of which 41 were ambulatory health care centers, 28 were private institutions, 27 were community hospitals, and 20 were university hospitals. On average, 2 linac accelerators and 2 megavoltage units were available in each institution. In 2014, a total of 36,830 patients were treated for benign diseases: 16,989 for degenerative diseases (peritendinitis humeroscapularis n = 2691; epicondylitis humeri n = 3788; heel spur n = 10,510); 14,936 for osteoarthritis (coxarthrosis n = 2230; gonarthrosis n = 2623; omarthrosis n = 2691; rhizarthrosis n = 2440; polyarthrosis n = 2297; others n = 2655); 1563 for hyperproliferative diseases (morbus Dupuytren n = 960; morbus Ledderhose n = 441; keloids n = 139; pterygium of the conjunctiva n = 3; other hyperproliferative diseases n = 20); 2440 for functional disorders (gynecomastia n = 843; Graves' disease n = 205; lymphatic fistula n = 178; heterotopic ossification prophylaxis n = 1214); 859 for stereotactic RT in the central nervous system (arteriovenous malformation n = 53; meningioma n = 425; acoustic neuroma n = 201; pituitary adenoma n = 131; others n = 49), and 43 for rare indications (pigmented villonodular synovitis n = 20 or vertebral hemangioma n = 23). The mean whole dose was <10 Gy in the treatment of degenerative disorders, 25 Gy for hyperproliferative diseases, 15 Gy for functional disorders, and <50 Gy for stereotactic RT. In 2014, RT had an important role in the treatment of benign diseases. Because treatment concepts are inherent, we recommend treatment based on the guidelines written by the German Cooperative Group on Benign Diseases.


Orthodontic forces add to nicotine-induced loss of periodontal bone : An in vivo and in vitro study.
Nicotine is considered an etiologic factor for chronic inflammatory phenomena within the periodontal ligament that may result in loss of periodontal attachment. Considering that smokers account for 26% of adult and 12% of adolescent patients in orthodontic practice, we performed in vivo and in vitro studies as to whether orthodontic forces may add to the nicotine-induced loss of periodontal bone. Fourteen male rats (Fischer 344 inbred) were used. Seven of these served as controls, while the other seven received daily subcutaneous injections of 1.89 mg L-nicotine per kg body weight. Both groups were exposed to orthodontic mesialization of the first two upper left molars using a NiTi closed-coil spring, the contralateral side serving as control. Periodontal bone loss was assessed by cone-beam computed tomography (CBCT). Human periodontal fibroblasts were stressed by compression (2 g/cm(2)) and/or nicotine (3/5/7.5 µmol), and the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin-6 (IL-6), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL) was determined at the transcriptional level by quantitative real-time polymerase chain reaction (qRT-PCR) and at the translational level by enzyme-linked immunosorbent assay (ELISA). In addition, differentiation of co-cultured murine RAW264.7 cells to osteoclast-like cells was quantified by tartrate-resistant acid phosphatase (TRAP) staining. Orthodontic force application in vivo led to a significant increase in nicotine-induced periodontal bone loss, and cell compression in vitro to increased COX-2, PGE2, IL-6, and RANKL expression, reduced OPG expression, and enhanced differentiation of RAW264.7 cells to osteoclast-like cells compared to nicotine alone. Additional loss of periodontal bone must be expected during orthodontic treatment of smokers. Clinicians should inform their patients of this increased risk and refrain from performing tooth movements before cessation of smoking.


The inner ear and the in vitro system.
The embryologic labyrinthine development of the CBA/CBA mouse occurs parallell in vivo and in vitro. Regarding post partum inner ears, either as cultured otocysts passing a corresponding time in vitro or inner ear explants of newborn/mature animals, the extracorporal system becomes unable to maintain specialized hair cell structures for more than a few days. The sensory cells themselves, however, survive for considerably longer time. Vestibular hair cells show sensory hair fusion. Cochlear hair cells loose their surface structures but the sensory hair rootlets penetrating into the cuticle are preserved. Post partum inner ears from the guinea pig reacted in a similar way in vitro as did labyrinths from the CBA/CBA mouse.


Relevance of electrograms and transient entrainment for antitachycardia devices.
Clearly, understanding what occurs during rapid pacing of tachyarrhythmias due to reentry with an excitable gap does not provide the panacea to the rapid pacing treatment of these arrhythmias. However, it does advance the field considerably, and provides insights which should be useful for the development of improved antitachycardia pacing techniques.


Genetic predisposition of alopecia areata in jordanians: A case-control study.
Alopecia areata (AA) is a common non-scarring hair loss disease of defined patterns with varied patches size and body sites. The etiology of AA has a complex basis of autoimmunity, environment, and genetic variations. The latter factor is found to play a crucial role in AA risk. Thus, this study aimed to investigate the potential impact of specific immune-related gene polymorphisms among a cohort of Jordanian patients, which was previously reported in other populations. Blood samples of AA patients and control subjects were collected for genomic DNA (gDNA) extraction. Targeted single nucleotide polymorphisms (SNPs) of MASP2, TLR1, CTLA4, and C11orf30 were genotyped in duplicate using the Sequenom MassARRAY® system (iPLEX GOLD). Genotype and allele analysis reveals statistical differences in TLR1 rs4833095 (allele C, P = 0.044), MASP2 rs2273346 (genotype AA, P = 0.0026), and C11orf30 rs2155219 (genotype GG, P = 0.0069) distribution. These findings present the significant contribution of genetic variations in AA susceptibility in the Jordanian population, which is infrequently studied.


Isolation and characterization of Magnetospirillum from saline lagoon.
Magnetotactic bacteria (MTB) are aquatic prokaryotes that orient themselves to earth's magnetic field with the help of intracellular organelle magnetosomes. Although many species of MTB have been identified, the isolation of MTB is a challenging task due to the lack of systematic isolation procedure and/or commercial media. In this study, we are reporting the isolation of magnetotactic spirillum from the Pulicat lagoon, India using a systematic and selective procedure. Sampling site was chosen on the basis of physicochemical properties of the ecosystem and the catalysed reporter deposition fluorescence in situ hybridization (CARD-FISH) analysis of sediment samples. In the current study, a combination of techniques including 'capillary racetrack' Purification and gradient cultivation resulted in the isolation of magnetotactic spirilla from aquatic sediments. Based on the 16S rRNA gene sequence analysis, the strain was identified as Magnetospirillum and was designated as Magnetospirillum sp. VITRJS1. The genes responsible for magnetosome formation (mamA, B, E, F, K, M, O, P, Q, T) were successfully detected using PCR amplification. The presence of cbbM gene confirmed that the isolate is chemolithoautotroph and utilises reduced sulphur as an electron source. Furthermore, magnetosomes extracted from VITRJS1 found to be cubo-octahedral in shape and 45 nm in size. Our results indicate that the systematic procedure using sediment analysis, CARD-FISH, and a combination of isolation methods enables the selective and rapid isolation of MTB from aquatic sediment sample.


Reliability and validity of a semi-structured DSM-based diagnostic interview module for the assessment of Attention Deficit Hyperactivity Disorder in adult psychiatric outpatients.
Despite growing recognition that the symptoms and functional impairments of Attention Deficit/Hyperactivity Disorder (ADHD) persist into adulthood, only a few psychometrically sound diagnostic measures have been developed for the assessment of ADHD in adults, and none have been validated for use in a broad treatment-seeking psychiatric sample. The current study presents the reliability and validity of a semi-structured DSM-based diagnostic interview module for ADHD, which was administered to 1194 adults presenting to an outpatient psychiatric practice. The module showed excellent internal consistency and interrater reliability, good convergent and discriminant validity (as indexed by relatively high correlations with self-report measures of ADHD and ADHD-related constructs and little or no correlation with other, non-ADHD symptom domains), and good construct validity (as indexed by significantly higher rates of psychosocial impairment and self-reported family history of ADHD in individuals who meet criteria for an ADHD diagnosis). This instrument is thus a reliable and valid diagnostic tool for the detection of ADHD in adults presenting for psychiatric evaluation and treatment.


Standardization of the Jendrassik maneuver in Achilles tendon tap reflex.
For many decades, the Jendrassik maneuver (JM) has been used as a reinforcement for stretch reflexes, although the underlying mechanism of this reinforcement is still not fully understood. Moreover, the term JM has been used for many different muscle contraction strategies as there is no fixed movement for the maneuver in the literature. In this study, we aimed to investigate the effects of clenched hand pull, teeth clenching, and their combined effects to reach standardization. Achilles tendon tap reflex responses in the soleus were recorded during rest (R), hand pull (HP), teeth clench (TC), and HP + TC combined, hereafter referred to as the JM. Reflex response amplitudes significantly increased during JM, HP, and TC in the soleus. HP and JM significantly changed the background activity in the soleus, but TC alone did not. These results suggest that dominantly presynaptic disinhibitory mechanisms may be responsible for the increase in the tendon tap reflex during HP, TC, and JM. Because the findings indicate that HP increases the background activity of the soleus, we suggest that researchers should use only TC during the Jendrassik maneuver to avoid any confounding background activity change.


Impact of protein acetylation in inflammatory lung diseases.
Chronic inflammatory lung diseases are characterized by increased expression of multiple inflammatory genes following activation by proinflammatory transcription factors, such as nuclear factor kappaB (NF-kappaB) and AP-1. Gene expression is, at least in part, regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity. Conversely gene repression is mediated via a combination of histone deacetylases (HDAC) and other corepressors. In asthma, the level of HAT activity is elevated in bronchial biopsies, whereas HDAC activity levels are only partially reduced and inhaled corticosteroids are able to reduce the increased HAT activity back to those seen in normal subjects. In contrast, in chronic obstructive pulmonary disease (COPD), there is a greater reduction in HDAC activity and HDAC2 expression but no difference in HAT activity. HAT and HDAC are also reported to modify a large and expanding number of nonhistone proteins, including nuclear import proteins, chaperones, cytoskeletal proteins, and other transcriptional factors, such as NF-kappaB and signal transducer and activation of transcription (STAT). Acetylation regulates several aspects of protein function and stability leading to differing effects on inflammatory gene expression and cell recruitment involved in the pathogenesis of inflammatory diseases. This review will examine the impact of acetylation on the function of key proteins involved in airway inflammatory disease and the effects of current therapies on acetylation status of key proteins. Further appreciation of the role of these changes may lead to the development of novel therapeutic approaches to inflammatory lung diseases that are currently difficult to treat.


Oral reactive capillary hemangiomas induced by SHR-1210 in the treatment of non-small cell lung cancer: a case report and literature review.
Antibodies to PD-1 and PD-L1 have remarkably improved the overall survival of many patients with advanced solid tumors. SHR-1210 is an anti-PD-1 monoclonal antibody. Dermatologic reactive capillary hemangiomas (RCH) were the most common and unique drug-related AEs of SHR-1210, but rare on oral mucosa and gastrointestinal mucosa. Herein we report a case of RCH occurred in oral mucosa during the clinical trials of SHR-1210 in the treatment of non-small cell lung cancer. A male in his 60 s with a history of non-small cell lung cancer received injection of anti-PD-1 monoclonal antibodies SHR-1210. The patient developed drug-related RCH on skin after the first injection and began to have gingival hyperplasia one year after the first injection which gradually increased in size and affect eating and speaking. Anti-PD-1 treatments were continued. After periodontal treatment, two oral lesions and one skin lesion were surgically removed. Similar histological manifestation was found in all three lesions as reactive capillary hemangiomas. All lesions had a good prognosis without recurrence on oral mucosa within one year after surgery. Oral reactive capillary hemangiomas could be induced by SHR-1210 in the treatment of non-small cell lung cancer. Surgical resection is an effective treatment with a good prognosis.


Stability of methylcellulose-based films after being subjected to different conservation and processing temperatures.
Methylcellulose films with and without sorbitol addition were developed. The major objective of this study was to attempt insights into the stability of the methylcellulose-based film properties after having been subjected to freezing, storage or a combination of both procedures. The importance of the sorbitol concentration and process temperature was also to be elucidated. As-prepared film solubility decreased at 100 °C, as a result of the methylcellulose thermogelation property when the samples were exposed to high temperatures. By analyzing the film pattern behavior and its properties 0.25% w/v sorbitol concentration turned out to be an inflexion point. The moisture content as well as the mechanical and thermal properties made this fact evident. Moreover the elastic modulus (Ec) and glass transition temperature (Tg) did not undergo significant changes for higher plasticizer concentrations. The methylcellulose film properties remained more stable in the presence of sorbitol, which would act as a protective agent due to its hydrogen bonding capacity. This stability is crucial for film and coating applications in the food industry.


Effect of primary and secondary radicals on chain breaks in ribosomal RNA in E. coli ribosomes.
Chain breaks in ribosomal RNA have been observed on gamma-radiation-induced inactivation of E. coli ribosomes. These breaks are caused by .OH and .H radicals, but not by e-aq and tertiary butanol-peroxy radicals.


Immunodeficient mice recover from infection with vaccinia virus expressing interferon-gamma.
Recombinant vaccinia viruses (VV)-encoding murine interferon-gamma (IFN-gamma) were constructed and the effect of virus-encoded IFN-gamma on the immune response towards VV in vivo investigated. In athymic nude mice and sublethally irradiated euthymic mice, IFN-gamma expression by VV enabled the mice to recover from the infection, whereas mice infected with the control virus died. In normal CBA/H mice also, the growth of VV was greatly reduced and it was cleared faster from mouse organs than the control virus. Natural killer (NK) cell responses in these mice were not enhanced suggesting that this recovery is not NK cell mediated. Other possible mechanisms and implications of this observation are discussed.


Dipstick urinalysis profile of an asymptomatic female group in south-east Nigeria.
Routine dipstick urinalysis is a useful and inexpensive method for the early detection of asymptomatic diseases. Our study was carried out to detect the prevalence of urinary abnormalities among an apparently asymptomatic healthy female group and emphasize the value of routine dipstick urinalysis. A cross-sectional study was carried out among second to sixth (final)-year female medical students of Nnamdi Azikiwe University, Nnewi campus between 8 and 30 September 2019. A total of 100 subjects were enrolled. First-morning midstream urine samples were collected and promptly tested with dipstick strips. Subjects with abnormal findings were informed and treated appropriately. In all, 54 (54%) of the subjects had urine abnormalities. Trace proteinuria was the commonest abnormality seen with a prevalence of 33%, followed by abnormal urine appearance (17%), leucocytes (14%), nitrites (8%) and urobilinogen (2%). Urine abnormalities were commoner in students who resided in the school hostel. Abnormal urine appearance was significantly associated with nitrites (0.003) and leucocytes (0.001). Routine dipstick urinalysis should be performed among students and apparently healthy individuals for early detection and diagnosis of renal diseases to facilitate quick interventions and prevent further progression.


Influence of the seagrass Thalassia hemprichii on coral reef mesocosms exposed to ocean acidification and experimentally elevated temperatures.
Ocean acidification (OA) and warming currently threaten coastal ecosystems across the globe. However, it is possible that the former process could actually benefit marine plants, such as seagrasses. The purpose of this study was to examine whether the effects of the seagrass Thalassia hemprichii can increase the resilience of OA-challenged coral reef mesocosms whose temperatures were gradually elevated. It was found that seagrass shoot density, photosynthetic efficiency, and leaf growth rate actually increased with rising temperatures under OA. Macroalgal growth rates were higher in the seagrass-free mesocosms, but the calcification rate of the model reef coral Pocillopora damicornis was higher in coral reef mesocosms featuring seagrasses under OA at 25 and 28 °C. Both the macroalgal growth rate and the coral calcification rate decreased in all mesocosms when the temperature was raised to 31 °C under OA. However, the variation in gross primary production, ecosystem respiration, and net ecosystem production in the seagrass mesocosms was lower than in seagrass-free controls, suggesting that the presence of seagrass in the mesocosms helped to stabilize the metabolism of the system in response to simulated climate change.


Presence of Clostridium difficile in pigs and cattle intestinal contents and carcass contamination at the slaughterhouse in Belgium.
The objective of this study was to evaluate the presence of Clostridium difficile in intestinal and carcass samples collected from pigs and cattle at a single slaughterhouse. C. difficile was isolated in 1% and 9.9% of the pig and cattle intestinal contents and in 7.9% and 7% of cattle and pig carcass samples respectively. A total of 19 different PCR-ribotypes were identified, among them types 078 and 014. Seven of 19 ribotypes correlated with the PCR-ribotypes involved in human C. difficile infections in Belgium. This study confirms that animals are carriers of C. difficile at slaughter and ribotypes are identical than those in humans, and that carcass contamination occurs inside the slaughterhouse.


A tissue-like neurotransmitter sensor for the brain and gut.
Neurotransmitters play essential roles in regulating neural circuit dynamics both in the central nervous system as well as at the peripheral, including the gastrointestinal tract1-3. Their real-time monitoring will offer critical information for understanding neural function and diagnosing disease1-3. However, bioelectronic tools to monitor the dynamics of neurotransmitters in vivo, especially in the enteric nervous systems, are underdeveloped. This is mainly owing to the limited availability of biosensing tools that are capable of examining soft, complex and actively moving organs. Here we introduce a tissue-mimicking, stretchable, neurochemical biological interface termed NeuroString, which is prepared by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer. NeuroString sensors allow chronic in vivo real-time, multichannel and multiplexed monoamine sensing in the brain of behaving mouse, as well as measuring serotonin dynamics in the gut without undesired stimulations and perturbing peristaltic movements. The described elastic and conformable biosensing interface has broad potential for studying the impact of neurotransmitters on gut microbes, brain-gut communication and may ultimately be extended to biomolecular sensing in other soft organs across the body.


Are imprecise methods obscuring a relation between fat and breast cancer?
Pooled analyses of cohort studies show no relation between fat intake and breast-cancer risk. However, food-frequency questionnaire (FFQ) methods used in these studies are prone to measurement error. We assessed diet with an FFQ and a detailed 7-day food diary in 13070 women between 1993 and 1997. We compared 168 breast-cancer cases incident by 2000 with four matched controls. Risk of breast cancer was associated with saturated-fat intake measured with the food diary (hazard ratio 1.22 [95% CI 1.06-1.40], p=0.005, per quintile increase in energy-adjusted fat intake), but not with saturated fat measured with the FFQ (1.10 [0.94-1.29], p=0.23). Dietary measurement error might explain the absence of a significant association between dietary fat and breast-cancer risk in cohort studies.


Roles of the 5' leader region of the ompA mRNA.
OmpA protein, a major outer membrane protein of Escherichia coli, is synthesized from a messenger RNA containing a 134-nucleotide 5' leader region. The role of this leader region in efficient ompA expression was investigated using a series of ompA-lacZ fusion plasmids. These plasmids differ in the amount of DNA encoding the ompA leader region which is fused to the lacZ structural gene. The fusion containing all but six nucleotides of the ompA leader produced the highest beta-galactosidase activity, while the fusion containing the shortest leader synthesized only 4% as much beta-galactosidase. Fusions with leaders intermediate in length produced between 6% and 24% of the activity found in the most efficient fusion. Quantitation of lacZ mRNA synthesis by DNA-RNA hybridization revealed differences in lacZ mRNA production reflecting the observed differences in beta-galactosidase activity. The primary effect of the ompA leader in maintaining high levels of mRNA is discussed in terms of the roles of mRNA secondary structure.


Data mining and molecular dynamics analysis to detect HIV-1 reverse transcriptase RNase H activity inhibitor.
HIV-1 is a deadly virus that affects millions of people worldwide. In this study, we aimed to inhibit viral replication by targeting one of the HIV-1 proteins and identifying a new drug candidate. We used data mining and molecular dynamics methods on HIV-1 genomes. Based on MAUVE analysis, we selected the RNase H activity of the reverse transcriptase (R.T) enzyme as a potential target due to its low mutation rate and high conservation level. We screened about 94,000 small molecule inhibitors by virtual screening. We validated the hit compounds' stability and binding free energy through molecular dynamics simulations and MM/PBSA. Phomoarcherin B, known for its anticancer properties, emerged as the best candidate and showed potential as an HIV-1 reverse transcriptase RNase H activity inhibitor. This study presents a new target and drug candidate for HIV-1 treatment. However, in vitro and in vivo tests are required. Also, the effect of RNase H activity on viral replication and the interaction of Phomoarcherin B with other HIV-1 proteins should be investigated.


SEOM SOGUG clinical guideline for treatment of kidney cancer (2022).
Renal cancer is the seventh most common cancer in men and the tenth in women. The aim of this article is to review the diagnosis, treatment, and follow-up of renal carcinoma accompanied by recommendations with new evidence and treatment algorithms. A new pathologic classification of RCC by the World Health Organization (WHO) was published in 2022 and this classification would be considered a "bridge" to a future molecular classification. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. Adjuvant treatment with pembrolizumab is an option for intermediate-or high-risk cases, as well as patients after complete resection of metastatic disease. More data are needed in the future, including positive overall survival data. Clinical prognostic classification, preferably IMDC, should be used for treatment decision making in mRCC. Cytoreductive nephrectomy should not be deemed mandatory in individuals with intermediate-poor IMDC/MSKCC risk who require systemic therapy. Metastasectomy can be contemplated in selected subjects with a limited number of metastases or long metachronous disease-free interval. For the population of patients with metastatic ccRCC as a whole, the combination of pembrolizumab-axitinib, nivolumab-cabozantinib, or pembrolizumab-lenvatinib can be considered as the first option based on the benefit obtained in OS versus sunitinib. In cases that have an intermediate IMDC and poor prognosis, the combination of ipilimumab and nivolumab has demonstrated superior OS compared to sunitinib. As for individuals with advanced RCC previously treated with one or two antiangiogenic tyrosine-kinase inhibitors, nivolumab and cabozantinib are the options of choice. When there is progression following initial immunotherapy-based treatment, we recommend treatment with an antiangiogenic tyrosine-kinase inhibitor. While no clear sequence can be advocated, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in the setting of metastatic RC.


In vivo inhibition of the tyrosinase of hamster melanoma with sodium diethyldithiocarbamate.
In vivo inhibition of the DOPA-oxydase activity of the soluble tyrosinase fraction of melanotic hamster melanoma is found after i.p. administration of diethyldithiocarbamate, with considerable increase in the content of SH-groups which probably play the role of free radical scavengers.


Two radical-dependent mechanisms for anaerobic degradation of the globally abundant organosulfur compound dihydroxypropanesulfonate.
2(S)-dihydroxypropanesulfonate (DHPS) is a microbial degradation product of 6-deoxy-6-sulfo-d-glucopyranose (sulfoquinovose), a component of plant sulfolipid with an estimated annual production of 1010 tons. DHPS is also at millimolar levels in highly abundant marine phytoplankton. Its degradation and sulfur recycling by microbes, thus, play important roles in the biogeochemical sulfur cycle. However, DHPS degradative pathways in the anaerobic biosphere are not well understood. Here, we report the discovery and characterization of two O2-sensitive glycyl radical enzymes that use distinct mechanisms for DHPS degradation. DHPS-sulfolyase (HpsG) in sulfate- and sulfite-reducing bacteria catalyzes C-S cleavage to release sulfite for use as a terminal electron acceptor in respiration, producing H2S. DHPS-dehydratase (HpfG), in fermenting bacteria, catalyzes C-O cleavage to generate 3-sulfopropionaldehyde, subsequently reduced by the NADH-dependent sulfopropionaldehyde reductase (HpfD). Both enzymes are present in bacteria from diverse environments including human gut, suggesting the contribution of enzymatic radical chemistry to sulfur flux in various anaerobic niches.


Copper deficiency: A potential model for determining the role of mitochondria in cardiac aging.
Heart mitochondria experience age-related declines in cytochrome c oxidase (CCO) activity and increases in the generation of reactive oxygen species (ROS) that may contribute to loss of cardiac function and the development of disease that occur with advancing age. In a manner similar to aging, copper deficiency also suppresses heart CCO activity and has cardiovascular consequences related to increased peroxidation. Food restriction is often used as a tool to study oxidative mechanisms of aging and the present study examines the potential of copper deficiency to model the role of mitochondria in cardiac aging by determining if the effect of food restriction on CCO activity and oxidative stress in heart mitochondria parallels its effect on cardiac mitochondria during aging. Overall, copper deficiency severely inhibited CCO activity and increased both Mn superoxide dismutase (MnSOD) and glutathione peroxidase (GPX) in isolated heart mitochondria. However, a 20% reduction in food intake by copper-deficient rats increased CCO activity by 65% and decreased MnSOD activity by 25% but had no effect in rats fed adequate copper. Copper deficiency also reduced the carbonyl content of 80-100 kDa mitochondrial proteins, but the reduction in carbonyl content was unaffected by food restriction. Food restriction did, however, completely prevent the enlargement of cardiac mitochondria in copper-deficient rats. Together, these findings indicate that copper deficiency induces mitochondrial antioxidant enzyme activity and hypertrophy in cardiac tissue in response to reduced CCO activity and that food restriction may counteract these changes by reducing oxidative stress. Because the action of food restriction on CCO activity and mitochondrially generated oxidative stress are similar in copper deficiency and aging, copper deficiency may serve as a short-term model for studying the potential roles of mitochondria in cardiac aging.


Development specifies, diversifies and empowers root immunity.
Roots are a highly organised plant tissue consisting of different cell types with distinct developmental functions defined by cell identity networks. Roots are the target of some of the most devastating diseases and possess a highly effective immune system. The recognition of microbe- or plant-derived molecules released in response to microbial attack is highly important in the activation of complex immunity gene networks. Development and immunity are intertwined, and immunity activation can result in growth inhibition. In turn, by connecting immunity and cell identity regulators, cell types are able to launch a cell type-specific immunity based on the developmental function of each cell type. By this strategy, fundamental developmental processes of each cell type contribute their most basic functions to drive cost-effective but highly diverse and, thus, efficient immune responses. This review highlights the interdependence of root development and immunity and how the developmental age of root cells contributes to positive and negative outcomes of development-immunity cross-talk.


Serotonin innervation in adult rat neostriatum. II. Ultrastructural features: a radioautographic and immunocytochemical study.
High-resolution radioautography after cerebroventricular administration of tritiated serotonin (5-HT) and PAP immunocytochemistry with an antiserum against 5-HT-glutaraldehyde conjugate (kindly donated by M. Geffard) were used in parallel to investigate the intrinsic and relational fine structural features of 5-HT axon varicosities (terminals) in the neostriatum of the adult rat. The uptake-labeled varicosities were examined in single thin sections from a paraventricular sector of neostriatum, whereas their immunostained counterparts were viewed in serial thin sections from the same paraventricular sector plus a dorsal neostriatal sector. The two approaches yielded complementary results in terms of varicosity dimensions, synaptic features and appositional relationships. Serotonin axon terminals were generally small and, as measured in immunostained material, even smaller in the dorsal than in the paraventricular neostriatum. Their internal features, best viewed in radioautographs, included small pleomorphic synaptic vesicles with occasional large granular vesicles and mitochondria. Junctional 5-HT terminals from both the paraventricular and the dorsal neostriatal sectors synapsed exclusively, and with equal frequency, on dendritic spines or shafts, almost always with asymmetrical membrane differentiations. The proportion of junctional varicosities, however, was very low in serial (immunocytochemical) as well as single (radioautographic) thin sections. Only 10-13% of 5-HT varicosities from either the paraventricular or the dorsal neostriatum exhibited a synaptic junction, in contrast with a junctional incidence of at least 70% for randomly selected axonal varicosities similarly sampled in the surrounding neuropil. Serotonin axon terminals, whether or not synaptic, were closely apposed to a variety of structures comprising mostly other axon terminals, dendritic spines and branches, but rarely neuronal somata. The synaptic and appositional features of immunostained 5-HT varicosities were similar for both the dorsal and the paraventricular neostriatum. In this context, it is likely that the effects of 5-HT in the neostriatum are exerted upon a multiplicity of cellular target sites in addition to the restricted number of dendritic spines and shafts synaptically contacted by this type of monoamine terminal.


Inhibition of homocytotropic antibody responses in adult inbred mice by previous feeding of the specific antigen.
Profound and prolonged states of specific immunologic tolerance were induced in adult mice of high-responder genetic background by a single exposure to moderate doses of the specific antigen by digestive route.


Echocardiographic Features of Cardiac Angiosarcomas: The Mayo Clinic Experience (1976-2013).
Cardiac angiosarcoma is the most common primary malignant cardiac tumor. The dismal prognosis and nonspecific symptomatology underscore the need for an accurate and cost-effective approach to the identification and characterization of this rare tumor. Mayo Clinic tissue registry archives were queried for all histologically confirmed cases of cardiac angiosarcoma (1976-2013) with available imaging data. Echocardiograms were retrospectively reviewed. Thirty-three cases of cardiac angiosarcoma were identified; of these, 17 had echocardiograms available (mean age, 46 years; six men). Transthoracic echocardiography (TTE) as the initial diagnostic test had 75% sensitivity for visualizing primary cardiac angiosarcoma (9/12 patients). Tumor extension into the pericardium was common and pericardial effusion was present in 15 patients (88%); however, pericardial fluid cytology was negative for malignancy in all tested patients (n = 15). Left ventricular ejection fraction (LVEF) was preserved in 16 patients (94%) (average LVEF, 62%). Right ventricular function was mildly reduced in two patients (12%) at initial presentation. Tricuspid valve obstruction was present in three patients (18%; mean diastolic gradient, 6.3 mmHg [range, 3-11 mmHg]). The sensitivity of TTE as the first diagnostic imaging modality compared favorably with computed tomography. Pericardial effusion was common, but pericardial fluid cytology was negative in all patients who underwent pericardiocentesis. The absence of a stalk was a universal finding that may help distinguish angiosarcoma from benign, primarily pedunculated tumors such as myxoma and papillary fibroelastoma.


Substance use and abuse among mentally retarded persons: a comparison of patients and a survey population.
Substance abuse among mentally retarded persons, first described 55 years ago, has received little or no attention by specialists in mental retardation. With deinstitutionalization, this problem has reappeared, often followed by victimization (i.e., assault, rape, robbery). In this study the demographic characteristics, family and childhood history, substance use patterns, and substance-related problems of 40 mild mentally retarded persons are compared with those of 40 mild mentally retarded persons without substance abuse. Similarities with substance abusers who are not mentally retarded are noted. Recommendations for alleviating this serious problem among mentally retarded persons are made.


Expanding the spectrum of neonatal-onset AIFM1-associated disorders.
Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.


[Long survival periods after therapy for metastatic or reccurrent cancer (author's transl)].
Out of 671 cases of various cancers, first seen for growing metastases and or recurrences (resectable cases being excluded) the 3 years survival rate has been 18 per cent (121 cases). This result was obtained by various combinations of chemotherapy and radiotherapy. It follows that advanced cases should not be abandoned without any attempt at control, and that earlier treatments in cases being at high risk for metastases would probably further increase such results.


Central mediation of the antihypertensive effect of pargyline in spontaneously hypertensive rats.
The monoamine oxidase (MAO) inhibitor pargyline induced a moderate (about 20 mm Hg) but persistent (48 h) decrease of systolic blood pressure in unanesthetized adult spontaneously hypertensive rats (SHR) but not in normotensive rats. The fall of blood pressure correlated with the blockade of norepinephrine (NE) deamination by brain homogenates. After an intracerebroventricular (icv) injection of 6-hydroxydopamine, which lowered brain NE content by about 70%, pargyline was unable to diminish arterial pressure. Blockade of central alpha-adrenoceptors by treatment with phentolamine (100 microgram icv) could either prevent or reverse the fall of blood pressure in SHR induced by pargylline. Moreover, a low dose of pargyline injected directly into the brain lowered arterial pressure. We conclude that the hypotensive action of pargylline in SHR appears to be the consequence of NE accumulating at an inhibitory alpha-adrenoceptor in brain.


Effect of salt type on hygroscopicity of a new cephalosporin S-3578.
Effect of salt type on hygroscopicity was evaluated using S-3578 salts. The hydration behavior of a sulfate and a nitrate salt of S-3578 were evaluated by powder X-ray diffraction (PXRD), simultaneous measurement of PXRD-differential scanning calorimetry (DSC), moisture sorption analysis, simultaneous measurement of thermogravimetric/differential thermal analyses, and solid state 13C-nuclear magnetic resonance (C-NMR). The sulfate salt incorporated two types of lattice water to form a monohydrate or a trihydrate. Additional water could also be absorbed as channel water to expand the lattice structure. The activation energy for dehydration was very high, probably due to steric hindrance in the lattice structure. The nitrate salt incorporated only one water molecule per compound as the lattice water. The additional water was absorbed as channel water as observed for the sulfate salt. X-ray diffractograms showed little dependence on the salt type under the ambient condition. The hydration number was likely to be affected by the size of the counter acids. The hygroscopicity of S-3578 salts was significantly altered by the salt type. The difference in the amount of the lattice water could be explained in terms of the difference in the molecular size of the counter acids.


Identification of oxysterol synthetic analogs as a novel class of late-stage inhibitors of herpes simplex virus 2 replication.
Genital herpes, most frequently caused by herpes simplex virus 2 (HSV-2) infection, is one of the most prevalent sexually transmitted infections. The current rationale for the treatment of HSV-2 infection involves nucleoside analogs (e.g. acyclovir) to suppress reactivation. Enzymatic oxysterols are endogenous 27-carbon atoms molecules produced by enzymatic cholesterol oxidation, and recently emerged as a broad-spectrum host targeting antivirals. In this study, we screened selected members of an in-house synthesized library of oxysterol analogs for their activity against HSV-2, identifying three compounds, named PFM064, PFM067, and PFM069, endowed with 50% effective concentrations (EC50) in the micromolar range, without exerting any apparent cytotoxicity. Moreover, the results obtained showed the ability of the novel derivatives to inhibit both cell-to-cell fusion induced by HSV-2, and the production of an intracellular viral progeny. Further experiments performed with PFM067 (which was selected for more-in-depth studies as the most effective synthetic analog) showed that these molecules act in a late stage of HSV-2 replicative cycle, by sequestering viral glycoproteins in the Golgi compartment, and likely inhibiting the nuclear egress of neo-synthetized viral capsids. Taken together, these results point to PFM067 as a promising chemical scaffold for the development of novel herpetic antivirals.


Quasi-Epitaxial Growth of Magnetic Nanostructures on 4H-Au Nanoribbons.
Phase engineering of nanomaterials is an effective strategy to tune the physicochemical properties of nanomaterials for various promising applications. Herein, by using the 4H-Au nanoribbons as templates, four novel magnetic nanostructures, namely 4H-Au @ 14H-Co nanobranches, 4H-Au @ 14H-Co nanoribbons, 4H-Au @ 2H-Co nanoribbons, and 4H-Au @ 2H-Ni nanoribbons, are synthesized based on the quasi-epitaxial growth. Different from the conventional epitaxial growth of metal nanomaterials, the obtained Co and Ni nanostructures possess different crystal phases from the Au template. Due to the large lattice mismatch between Au and the grown metals (i.e., Co and Ni), ordered misfit dislocations are generated at the Co/Au and Ni/Au interfaces. Notably, a new super-structure of Co is formed, denoted as 14H. Both 4H-Au @ 14H-Co nanobranches and nanoribbons are ferromagnetic at room temperature, showing similar Curie temperature. However, their magnetic behaviors exhibit distinct temperature dependence, resulting from the competition between spin and volume fluctuations as well as the unique geometry. This work paves the way to the templated synthesis of nanomaterials with unconventional crystal phases for the exploration of phase-dependent properties.


Double-blind controlled trial of the Garren-Edwards gastric bubble: an adjunctive treatment for exogenous obesity.
Since its approval by the Food and Drug Administration in September 1985, the Garren-Edwards gastric bubble has been extensively used as an adjunct to diet and behavioral modification in the treatment of exogenous obesity. In an attempt to evaluate the efficacy of the Garren-Edwards gastric bubble, a double-blind crossover study was undertaken. Ninety patients were randomized into three groups: bubble-sham, sham-bubble, and bubble-bubble in two successive 12-wk periods. Sixty-one patients completed the entire 24-wk study. All groups participated in ongoing diet and behavioral modification therapy in a free-standing obesity program, the members of which were blinded to randomization arms. All patient groups lost weight during this study. The mean cumulative weight loss in pounds at 12 wk was as follows: bubble-sham = 19, sham-bubble = 12, and bubble-bubble = 8; and at 24 wk: bubble-sham = 23, sham-bubble = 16, and bubble-bubble = 18. The mean cumulative change in body mass index (kg/m2) at 12 wk was as follows: bubble-sham = -3.1, sham-bubble = -2.3, and bubble-bubble = -2.9; and at 24 wk: bubble-sham = -3.1, sham-bubble = -3.0, and bubble-bubble = -3.3. Although weight loss occurred more consistently in patients with a Garren-Edwards gastric bubble, there were no significant differences between any of the three groups at 12 or 24 wk with respect to weight loss or change in body mass index. The major part of the weight loss noted during this study occurred during the first 12-wk period, irrespective of therapy (bubble or sham). Side effects observed during this study included gastric erosions (26%), gastric ulcers (14%), small bowel obstruction (2%), Mallory-Weiss tears (11%), and esophageal laceration (1%). We conclude that, in this study, the use of a Garren-Edwards gastric bubble did not result in significantly more weight loss than diet and behavioral modification alone in the management of exogenous obesity, and it may result in significant morbidity.


Interleukin-2 at different concentrations induces the growth of selective lymphoid cells.
The effects of low and high doses of recombinant interleukin-2 (rIL-2) on cultured peripheral blood mononucleated cells are reported with the aim to show the effects of this immunomodulator in different conditions. The proliferation of various cell types at different IL-2 concentrations was investigated and ultrastructural and enzymatic studies were performed. The data obtained indicate that grade and type of cell stimulation induced by IL-2 is correlated to the dose employed.


Factors associated with motor and cognitive deficits in children after intrapartum fetal hypoxia.
Sixty children with biochemical evidence of intrapartum fetal hypoxia were studied to define the factors which distinguish the children with deficits from those without deficits of motor and cognitive development. Follow-up assessment included growth measures, neurological examination, Bayley Scales of Infant Development, and a modified Uzgiris and Hunt Scale. Eight children (13%) had a major deficit and 10 children (16%) had a minor deficit at 1 year. Children with deficits had an episode of hypoxia that was more severe and prolonged and, subsequent to delivery, a greater incidence of severe respiratory complications, apnea, and newborn encephalopathy. No other significant risk factors were identified. It is concluded that an episode of hypoxia less than one hour may occur without subsequent deficits. However, an episode of hypoxia in excess of 1 hour resulting in a metabolic acidosis of the order of 25 mEq/L will be followed by motor and cognitive deficits in approximately 50% of children.


Magnetic resonance spectroscopy in mild cognitive impairment: systematic review and meta-analysis.
Research using proton magnetic resonance spectroscopy (MRS) can potentially elucidate metabolite changes representing early degeneration in Mild Cognitive Impairment (MCI), an early stage of dementia. We integrated the published literature using meta-analysis to identify patterns of metabolite changes in MCI. 29 MRS studies (with a total of 607 MCI patients and 862 healthy controls) were classified according to brain regions. Hedges' g was used as effect size in a random effects model. N-Acetyl Aspartate (NAA) measures were consistently reduced in posterior cingulate (PC), hippocampus, and the paratrigonal white matter (PWM). Creatine (Cr) concentration was reduced in the hippocampus and PWM. Choline (Cho) concentration was reduced in the hippocampus while Cho/Cr ratio was raised in the PC. Myo-inositol (mI) concentration was raised in the PC and mI/Cr ratio was raised in the hippocampus. NAA/mI ratio was reduced in the PC. NAA may be the most reliable marker of brain dysfunction in MCI though mI, Cho, and Cr may also contribute towards this.


Utility of contrast enema to assess anastomotic integrity and the natural history of radiological leaks after low rectal surgery: systematic review and meta-analysis.
There is no clear consensus on how to assess low rectal anastomotic integrity and patency prior to reversal of de-functioning stoma. The aim of this systematic review was to assess the utility of contrast enema (CE) in this context and to clarify the natural history of radiological leaks. Keyword search of electronic databases (Embase, MEDLINE, Cochrane Library, Google Scholar) and bibliographic cross-referencing were performed to identify appropriate studies. Data extraction and synthesis was performed with the primary outcomes being the sensitivity and specificity of CE for detecting clinically significant abnormalities. Statistical analysis was performed using Open Meta-Analyst software. Narrative review of outcomes including those of clinical and radiological leaks was also undertaken. A total of 1,142 CE from 11 articles were included in the final meta-analysis. CE had high specificity (95.4; 95 % confidence interval = 92.0-97.4) and negative predictive value (98.4; 97.4-99.1) and moderate sensitivity (79.9; 63.9-89.9) and positive predictive value (64.6; 55.5-72.9) for the detection of clinically significant anastomotic problems. There was a high degree of correlation between CE and clinical examination findings (96.7 %). Occult radiological leaks were seen in 5.7 % of CE, and all but one (97 %) eventually underwent successful reversal. Only three quarters of patients with clinical leak underwent successful reversal. CE is effective at excluding clinically significant anastomotic problems, especially after clinical anastomotic leaks. However, false positive results can be observed in asymptomatic patients, and it is unclear how much additional information CE provides over clinical assessment in the low uncomplicated anastomosis.


Total saponins extracted from Abrus cantoniensis Hance suppress hepatitis B virus replication in vitro and in rAAV8-1.3HBV transfected mice.
Hepatitis B, an infectious disease caused by hepatitis B virus (HBV), is still a serious problem affecting global public health. Abrus cantoniensis Hance (AC), a traditional Chinese medicinal herb, has been used as a folk medicine for treating hepatitis in China from ancient times. However, its active ingredients are still unclear. Our previous study indicated that saponins extracted from AC (ACS) were the active anti-HBV ingredients in AC. This study aimed to further investigate the anti-HBV effect of ACS in vitro and in vivo. HepG2.2.15 cells which consecutively produce HBV DNA and HBV antigens were used for in vitro test, and C57BL/6 mice infected by a recombinant adeno-associated virus 8 vector carrying 1.3 copies of HBV genome (rAAV8-HBV1.3) were used for in vivo test. The histopathological changes and the immune indices were evaluated in mice model. Genechip was conducted to identify genes and pathways regulated by ACS in HepG2.2.15 cells. In this study, we confirmed that ACS treatment prominently inhibited production of HBV DNA, Hepatitis Be Antigen (HBeAg), and Hepatitis B surface antigen (HBsAg) in HepG2.2.15 cells. ACS treatment also decreased serum HBsAg, HBeAg, and HBV DNA level in rAAV8-1.3HBV transfected mice, which is in accordance with the in vitro results. Moreover, HBV infection-induced liver inflammation was significantly relieved by ACS, which could be observed in H&E staining and immunohistochemistry of HBcAg. ACS treatment elevated IFN-γ level in mice serum and increased CD4+ T cell percentage in splenocytes. KEGG pathway analysis showed that phenylalanine metabolism pathway and tyrosine metabolism pathway were greatly regulated by ACS treatment. ACS exerted potent inhibitory effects on HBV replication both in vivo and in vitro, which may provide basis for its potential clinical usage.


An improved conjugation method for controlled covalent coupling of synthetic peptides to proteins using glutaraldehyde in a dialysis method.
Controlled and efficient conjugation of synthetic peptides to proteins, for use in immunization or in assay procedures, is a prerequisite for the immunological applications of synthetic peptides. This study describes a new method of conjugating synthetic peptides to proteins in such a way that no homopolymers of synthetic peptides or proteins occur. To achieve this, the protein is first activated with glutaraldehyde and subsequently excess glutaraldehyde is removed. Then coupling of the synthetic peptide to the activated protein occurs while subsequently the surplus reactive glutaraldehyde groups on the protein are blocked with lysine. Excess free peptide and lysine is then removed by dialysis. This improvement not only results in better defined conjugates when compared to classical glutaraldehyde coupling, but also in the consumption of smaller amounts of synthetic peptide during conjugate formation. When used for immunization we obtained similar and sometimes even better responses with the glutaraldehyde based conjugates than with succinimidyl (MBS) conjugates of the same peptides. The performance of the modified conjugates in ELISA procedures, immunization and immunocytochemistry suggests that they are superior to conjugates formed by classical glutaraldehyde coupling.


Body image and body concept in patients with chronic tinnitus.
The literature leads us to assume that people suffering from tinnitus may also have negative feelings about their body concept and body image. This pilot study aimed to investigate patients with chronic tinnitus for the presence of disturbed body concept and body image, taking into account the subjective degree of distress and any depression. Sixty-five patients with chronic tinnitus (members of a support group) were interviewed concerning the subjective distress caused by their tinnitus, their body image and any depression. Overall, the study collective showed significantly less "vitality and body dynamics," "attractiveness/self-confidence" and was less pleased with "emphasis on the appearance of one's own body" than was a predetermined random sample of healthy controls. Comparison of those patients reporting severe tinnitus and those with mild tinnitus showed the former to suffer from significantly greater "uncertainty and concern" with regard to their bodies. In practice, problems involving a person's body image should be given greater consideration during examination and when planning treatment and, for example, therapy should incorporate body-related exercises.


Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma.
Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca2+ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca2+ channels has shown promise in preclinical studies, but clinical trials have been disappointing and combinatorial approaches are needed. We assessed efficacy of multiple combinations of three Ca2+ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca2+ channels; oxidised adenosine-triphosphate (oxATP) to inhibit purinergic P2X7 receptors and/or 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid (INQ) to inhibit Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca2+ channel inhibitors delivered in combination significantly preserved visual function, as assessed using the optokinetic nystagmus visual reflex, at 3 months after injury. Preservation of retinal ganglion cells was partial and is unlikely to have accounted for differential effects on function. A range of the Ca2+ channel inhibitor combinations prevented swelling of optic nerve vulnerable to secondary degeneration. Each of the treatments involving lomerizine significantly increased the proportion of axons with normal compact myelin. Nevertheless, limiting decompaction of myelin was not sufficient for preservation of function in our model. Multiple combinations of Ca2+ channel inhibitors reduced formation of atypical node/paranode complexes; outcomes were not associated with preservation of visual function. However, prevention of lengthening of the paranodal gap that was only achieved by treatment with the three Ca2+ channel inhibitors in combination was an important additional effect that likely contributed to the associated preservation of the optokinetic reflex using this combinatorial treatment strategy.


Nurse Practitioners to Docs, Lawmakers: Give Us Our Independence.
And that means full scope of practice as primary care providers. Medical societies hate the idea and think that nurse practitioners need to be tethered securely to a physician office in order to ensure top-notch care. Nurse practitioners counter that they can help shore up primary care.


A practical approach to the hepatobiliary kinetics of 99mTc-HIDA. Clinical validation of the method and a preliminary report on its use for parametric imaging.
99mTc-diethyl-HIDA cholescintigraphy was performed on 24 patients with histologically proven liver disease and on 10 normal adult subjects. Liver mass transport of HIDA was interpreted with the aid of a probabilistic model, assuming that the tracer particles undergo mixed random walks with drifts. The radiohepatograms were thus fitted with a gamma-variate function and the fitting parameters were evaluated as estimates of the severity of the disease. These parameters, together with the transit times, were also used to generate parametric images of liver function. The advantages of this approach are discussed and the following conclusions are drawn: (1) The gamma-fit is highly satisfactory with any type of experimental curve (0.98 less than r less than 1). (2) The parameters derived from the gamma-fit make it possible to objectively assess the extent of liver functional impairment. (3) Parametric imaging of the liver mass transport of HIDA is easily implemented, but still more experience is needed to assess its impact on patient care.


Triple primary lung cancer: a case report.
The risk of developing lung cancer is increased in smokers, patients with chronic obstructive pulmonary disease, individuals exposed to environmental carcinogens, and those with a history of lung cancer. Automobile exhaust fumes containing carcinogens are a risk factor for lung cancer. However, we go through life unaware of the fact that automobile exhaust is the cause of cancer. Especially, in lung cancer patient, it is important to search out pre-existing risk factors and advice to avoid them, and monitor carefully for recurrence after treatment. This is the first report of a case with triple lung cancers with different histologic types at different sites, observed in a 76-year-old parking attendant. The first adenocarcinoma and the second squamous cell carcinoma were treated with stereotactic radiosurgery because the patient did not want to undergo surgery. Although the patient stopped intermittent smoking after the diagnosis, he continued working as a parking attendant in the parking lot. After 29 months from the first treatment, the patient developed a third new small cell lung cancer; he was being treated with chemoradiation. New mass after treatment of lung cancer might be a multiple primary lung cancer rather than metastasis. Thus, precision evaluation is important. This paper highlights the risk factors for lung cancer that are easily overlooked but should not be dismissed, and the necessity of discussion with patients for the surveillance after lung cancer treatment. We should look over carefully the environmental carcinogens already exposed, and counsel to avoid pre-existing lung cancer risk factors at work or residence in patients with lung cancer.


Economic analysis of participation in physical activity in England: implications for health policy.
Changing the relative price of (in) activity is an important tool for health policies. Nonetheless, to date, analyses of correlates of physical activity (PA) have excluded the notion of price. Using the first nationwide dataset on prices of PA for England, we explore for the first time how money and time prices are associated with PA (in general) and specific activities. A nationally representative telephone follow-up survey to Health Survey for England (HSE) 2008 was undertaken in 2010. The sample covered individuals who reported to have undertaken some PA in the HSE 2008. Questions focussed on: ex-post money and time prices; type and quantity of PA; perceived benefits of PA and socio-economic details. Count regression models (all activities together, and swimming, workout, walking separately) were fitted to investigate the variation in quantity of PA. Of 1683 respondents, 83% participated in PA (one or more activities), and spent an average of £2.40 per occasion of participation in PA and 23 minutes travelling. Participation in PA was negatively associated with money prices per occasion (i.e. family member/child care fees, parking fees, and facility charges) and travel time price. Participation in PA was more sensitive to travel time price than money price. Among the specific activities, the money price effect was highest for swimming with a 10% higher price associated with 29% fewer occasions of swimming; followed by workout (3% fewer occasions) and walking (2% fewer occasions). Only swimming and workout were sensitive to travel time price. People who felt doing PA could help them 'get outdoors', 'have fun', or 'lose weight' were likely to do more PA. Two main policy implications emerge from the findings. First, the results support the notion that positive financial incentives, e.g. subsidising price of participation, could generally lead to an increase in quantity of PA among those already exercising. Second, such policies could lead to desired policy goals if implemented at an individual activity level (e.g. 50% subsidy on swimming entrance charges) rather than a blanket implementation (e.g. subsidising average entrance charges across all activities by 50%).


Developmental deltamethrin: Sex-specific hippocampal effects in Sprague Dawley rats.
Pyrethroid pesticides are widely used and can cause long-term effects after early exposure. Epidemiological and animal studies reveal associations between pyrethroid exposure and altered cognition following prenatal and/or neonatal exposure. However, little is known about the cellular effects of such exposure. Sprague Dawley rats were gavaged with 0 or 1.0 mg/kg deltamethrin (DLM), a Type II pyrethroid, in corn oil (dose volume 5 mL/kg) once per day from postnatal day (P) 3-20 and assessed shortly after dosing ended or as adults. No effects of DLM exposure were found on striatal dopaminergic markers, nor on AMPA receptor subunits or on NMDA-NR1. However, DLM increased NMDA-NR2A and decreased NMDA-NR2B levels in the hippocampus, in males but not females. Additionally, adult hippocampal CA1 long-term potentiation was increased in DLM-treated males but not females. Potassium stimulated extracellular glutamate release in the hippocampus was not affected using in vivo microdialysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed increased apoptotic cells in the dentate gyrus of male rats, in the absence of changes in cleaved caspase-3 at P21. Proinflammatory cytokines interferon gamma trended up in striatum, interleukin-1β trended down in nucleus accumbens, IL-13 trended up in hippocampus, and keratinocyte chemoattractant/human growth-regulated oncogene (KC/GRO or CXCL1) was significantly increased in the hippocampus in male DLM-treated rats on P20. The data point to the developing hippocampus as a susceptible region to DLM-induced adverse effects.


Subregional prefrontal cortex recruitment as a function of inhibitory demand: an fMRI metanalysis.
Convergent studies corroborated the idea that the right prefrontal cortex is the crucial brain region responsible for inhibiting our actions. However, which sub-regions of the right prefrontal cortex are involved is still a matter of debate. To map the inhibitory function of the sub-regions of the right prefrontal cortex, we performed Activation Likelihood Estimation (ALE) meta-analyses and meta-regressions (ES-SDM) of fMRI studies exploring inhibitory control. Sixty-eight studies (1684 subjects, 912 foci) were identified and divided in three groups depending on the incremental demand. Overall, our results showed that higher was the inhibitory demand based on the individual differences in performances, more the upper portion of the right prefrontal cortex was activated to achieve a successful inhibition. Conversely, a lower demand of the inhibitory function, was associated with the inferior portions of the right prefrontal cortex recruitment. Notably, in the latter case, we also observed activation of areas associated with working memory and responsible for cognitive strategies.


Structure of the shell and tertiary membranes of eggs of softshell turtles (Trionyx spiniferus).
Eggs of the turtle Trionyx spiniferus are rigid, calcareous spheres averaging 2.5 cm in diameter. The eggshell is morphologically very similar to avian eggshells. The outer crystalline layer is composed of roughly columnar aggregates, or shell units, of calcium carbonate in the aragonite form. Each shell unit tapers to a somewhat conical tip at its base. Interior to the crystalline layer are two tertiary egg membranes: the outer shell membrane and the inner shell membrane. The outer shell membrane is firmly attached to the inner surface of the shell, and the two membranes are in contact except at the air cell, where the inner shell membrane separates from the outer shell membrane. Both membranes are multi-layered, with the inner shell membrane exhibiting a more fibrous structure than the outer shell membrane. Numerous pores are found in the eggshell, and these generally occur at the intersection of four or more shell units.


Aminolevulinic Acid Photodynamic Therapy in the Treatment of Erosive Pustular Dermatosis of the Scalp: A Case Series.
Erosive pustular dermatosis of the scalp (EPDS) is an inflammatory skin condition that develops on sun-damaged skin in older individuals. Patients with EPDS present a therapeutic challenge because medical treatments and surgical modalities have met with limited success. Methyl aminolevulinate photodynamic therapy has been effective in 1 case but induced the disease in others. Eight patients with EPDS with mean (range) age 84 (67-93) years underwent gentle curettage of the hyperkeratotic lesions followed by aminolevulinic acid photodynamic therapy (PDT) 1 to 2 weeks later. Lesions resolved in 6 patients, whereas 2 patients had residual lesions at 6-week follow-up and underwent a second cycle of curettage and aminolevulinic acid PDT with resolution. One patient experienced a partial recurrence 5 months after the procedure and was successfully retreated with curettage + aminolevulinic acid PDT. No adverse effects were noted, and patients were satisfied with the treatment. This series of patients demonstrated EPDS successfully treated with PDT. Lesions resolved in all patients with a protocol that included curettage followed by aminolevulinic acid PDT. Therefore, this protocol represents an efficacious modality for EPDS.


Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E.
Apolipoprotein E (apoE) is a multifunctional plasma glycoprotein involved in lipoprotein metabolism and a range of cell signalling phenomena. ApoE-deficient (apoE(-/-)) mice exhibit severe hypercholesterolaemia and are an excellent model of human atherosclerosis. ApoE somatic gene transfer and bone marrow transplantation in apoE(-/-) mice results in reversal of hypercholesterolaemia, inhibition of atherogenesis and regression of atherosclerotic plaque density. Replication defective adeno-associated virus vectors (rAAVs) are an attractive system currently in clinical trial for muscle-based heterologous gene therapy to express secreted recombinant plasma proteins. Here we have applied rAAV transduction of skeletal muscle to express wild-type (epsilon3) and a defective receptor-binding mutant (epsilon2) human apoE transgene in apoE(-/-) mice. In treated animals, apoE mRNA was present in transduced muscles and, although plasma levels of recombinant apoE fell below the detection levels of our ELISA (ie <10 ng/ml), circulating antibodies to human apoE and rAAV were induced. Up to 3 months after a single administration of rAAV/apoE3, a significant reduction in atherosclerotic plaque density in aortas of treated animals was observed (approximately 30%), indicating that low-level rAAV-mediated apoE3 expression from skeletal muscle can retard atherosclerotic progression in this well-defined genetic model.


Extrusion of the medial meniscus under a weight-loading condition in early knee osteoarthritis: an investigation using special upright magnetic resonance imaging.
Whether the medial meniscus morphology and movement occur under upright loading conditions in early knee osteoarthritis (OA) or medial meniscus posterior root tear (MMPRT) remains unknown. This study aimed to evaluate the medial and anteroposterior extrusion of the medial meniscus under unloaded and upright-loaded conditions in patients with early knee OA. Twelve patients with early knee OA and 18 healthy adult volunteers participated in this study. Magnetic resonance imaging using special equipment was performed with the participants in the unloaded and upright-loaded conditions. Medial, anterior, and posterior extrusions of the medial meniscus against the tibial edge were evaluated and compared between the early knee OA and healthy adult control groups. Additionally, 12 patients in the early knee OA group were divided into 2 subgroups based on whether MMPRT was observed, and the extrusion of the medial meniscus was compared. The amount of medial extrusion of the medial meniscus in both the unloaded and upright-loaded conditions was significantly greater in the early knee OA group than in the control group (unloaded: 2.6 ± 1.0 mm vs 0.7 ± 0.5 mm; upright-loaded: 3.7 ± 0.9 mm vs 1.8 ± 0.8 mm). Similarly, the anterior and posterior extrusion of the medial meniscus in the upright-loaded condition was significantly larger in the early knee OA group (anterior: 4.6 ± 1.0 mm vs 3.7 ± 1.1 mm; posterior: -3.4 ± 1.1 mm vs -4.6 ± 1.6 mm). However, no difference was observed in meniscal extrusion between unloaded and upright-loaded conditions. The posterior extrusion of the medial meniscus in the upright-loaded condition was significantly greater in MMPRT cases than in non-MMPRT cases in the early knee OA group (MMPRT: -2.7 ± 1.1 mm; non-MMPRT -4.1 ± 1.5 mm). In early knee OA, significantly large meniscal extrusions of the medial meniscus in both unloaded and upright-loaded conditions were found compared with healthy adults. Among patients with early knee OA, those with MMPRT showed a large posterior extrusion of the medial meniscus in the upright-loaded condition compared with those without MMPRT. Level IV.


Concise synthesis of α-galactosyl ceramide from D-galactosyl iodide and D-lyxose.
α-Galactosyl ceramide is synthesized from d-lyxose in 32% overall yield in five steps. The short and efficient protocol involves a one-pot protection and glycosidation of D-lyxose with D-galactosyl iodide as a key step. The α-linked disaccharide obtained was subsequently transformed into α-galactosyl ceramide in four steps involving Z-selective Wittig olefination at C-1, stereo-inversion at C-4 using azide, one-pot reduction of azide and amidation, and global deprotection.


Flow-controlled ventilation during EVLP improves oxygenation and preserves alveolar recruitment.
Ex vivo lung perfusion (EVLP) is a widespread accepted platform for preservation and evaluation of donor lungs prior to lung transplantation (LTx). Standard lungs are ventilated using volume-controlled ventilation (VCV). We investigated the effects of flow-controlled ventilation (FCV) in a large animal EVLP model. Fourteen porcine lungs were mounted on EVLP after a warm ischemic interval of 2 h and randomized in two groups (n = 7/group). In VCV, 7 grafts were conventionally ventilated and in FCV, 7 grafts were ventilated by flow-controlled ventilation. EVLP physiologic parameters (compliance, pulmonary vascular resistance and oxygenation) were recorded hourly. After 6 h of EVLP, broncho-alveolar lavage (BAL) was performed and biopsies for wet-to-dry weight (W/D) ratio and histology were taken. The left lung was inflated, frozen in liquid nitrogen vapors and scanned with computed tomography (CT) to assess regional distribution of Hounsfield units (HU). All lungs endured 6 h of EVLP. Oxygenation was better in FCV compared to VCV (p = 0.01) and the decrease in lung compliance was less in FCV (p = 0.03). W/D ratio, pathology and BAL samples did not differ between both groups (p = 0.16, p = 0.55 and p = 0.62). Overall, CT densities tended to be less pronounced in FCV (p = 0.05). Distribution of CT densities revealed a higher proportion of well-aerated lung parts in FCV compared to VCV (p = 0.01). FCV in pulmonary grafts mounted on EVLP is feasible and leads to improved oxygenation and alveolar recruitment. This ventilation strategy might prolong EVLP over time, with less risk for volutrauma and atelectrauma.


The First Cardiac Operation Using Cardiopulmonary Bypass.
The first open heart operation ever performed was by Clarence Dennis on April 5, 1951, at the University of Minnesota. For several years he had worked developing a heart-lung machine. The operation was on a young girl considered to have an ostium secundum atrial septal defect, but at the procedure a large ostium primum was identified instead. It could not be repaired, and the child died. The anatomic details of this heart have not been previously presented. For historical purposes, the clinical history, intraoperative course, and pathologic details will be discussed and shown.


Topical negative pressure therapy of a sternotomy wound increases sternal fluid content but does not affect internal thoracic artery blood flow: assessment using magnetic resonance imaging.
Topical negative pressure therapy has excellent healing effects in poststernotomy mediastinitis. Topical negative pressure therapy reduces bacterial counts, increases wound edge microvascular blood flow and granulation tissue formation, and facilitates healing. No study has yet been performed to examine the effect of topical negative pressure on the blood and fluid content in the sternal bone marrow, which is a crucial component in osteitis. Eight pigs underwent median sternotomy, left internal thoracic artery harvesting, followed by topical negative pressure treatment. Magnetic resonance imaging was used to quantify both tissue fluid and/or blood content (T2-weighted short tau inversion recovery [T2-STIR]) and internal thoracic artery blood flow (flow quantification). Before application of topical negative pressure, the T2-STIR signal intensity ratio was lower for the left than for the right hemisternum (left, 1.3; right, 2.6), indicating lower levels of tissue fluid content on the left, devascularized side. On application of topical negative pressure, the T2-STIR signal intensity ratio increased immediately for both the sternal bone and the pectoral muscle (left hemisternum after 4 minutes of topical negative pressure: 2.3), leveled off after 4 minutes, and remained unchanged for the ensuing 40 minutes, suggesting movement of fluid and/or blood into the tissue of the wound edge. Topical negative pressure did not affect blood flow in the right internal thoracic artery. T2-STIR measurements show that topical negative pressure increases sternotomy wound edge tissue fluid and/or blood content. Topical negative pressure creates a pressure gradient that presumably draws fluid from the surrounding tissue to the sternal wound edge and into the vacuum source. This "endogenous drainage" may be one possible mechanism by which osteitis is resolved by topical negative pressure in poststernotomy mediastinitis.


Management of premature rupture of membranes before 25 weeks.
The aim of our study was to define the benefits and risks related to expectant management in the midtrimester rupture of membranes and to assess the prognostic factors in order to give objective informations to parents facing these obstetrical situations. We conducted a retrospective study. The study population included 49 patients with premature rupture of membranes at 16-23 weeks' gestation during the period January 1998-June 2003. The main criterion for judgement was neonate survival. Statistical analysis included chi2-test for the qualitative variables and Student's test for the quantitative variables. The threshold for significance was 5%. Twenty couples out of 49 chose medical termination of pregnancy. Among the 29 other pregnancies, the mean latency period was 2.1 weeks. The mean gestational age at delivery was 23.2 weeks. Nineteen patients were delivered after 22 weeks. The main prognostic factors were the initial amniotic fluid index (2.9 cm versus 0.8 cm) (p=0.042) and gestational age at delivery (26.7 weeks versus 22.6 weeks) (p<0.001). About 2% of the pregnancies were complicated by maternal infection. Eighty-three percent of the survivors had neonatal respiratory distress syndrome. 41.2% of them presented sepsis. We observed no cases of severe intraventricular haemorrhage. The number of infants born after 24 weeks of gestation and still alive at 1 week was 12, representing 24% of pregnancies and 63% of the infants born after 24 weeks. Expectant management can be widely suggested to patients. However, termination of pregnancy is acceptable, in cases with a poor prognosis including anamnios and premature rupture of membranes before 21 weeks.


Biliary parasites: diagnostic and therapeutic strategies.
Parasitic infections of the biliary tract are a common cause of biliary obstruction in endemic areas. This article focuses on primary biliary parasites: Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Dicrocoelium dendriticum, Fasciola hepatica, and Fasciola gigantica. Tropical and subtropical countries have the highest incidence and prevalence of these infections. Diagnosis is made primarily through direct microscopic examination of eggs in the stool, duodenal, or bile contents. Radiologic imaging may show intrahepatic ductal dilatation, whereas endoscopic retrograde cholangiopancreatography can be used diagnostically and therapeutically. However, oral treatment is inexpensive and effective for most of these parasites and can prevent untoward consequences. Primary and alternative treatments are available and are reviewed in this article.


ErbB4 in parvalbumin-positive interneurons mediates proactive interference in olfactory associative reversal learning.
Consolidated memories influence later learning and cognitive processes when new information is overlapped with previous events. To reveal which cellular and molecular factors are associated with this proactive interference, we challenged mice with odor-reward associative learning followed by a reversal-learning task. The results showed that genetical ablation of ErbB4 in parvalbumin (PV)-positive interneurons improved performance in reversal-learning phase, with no alteration in learning phase, supporting that PV interneuron ErbB4 is required for proactive interference. Mechanistically, olfactory learning promoted PV interneuron excitatory synaptic plasticity and direct binding of ErbB4 with presynaptic Neurexin1β (NRXN1β) and postsynaptic scaffold PSD-95 in the prefrontal cortex. Interrupting ErbB4-NRXN1β interaction impaired network activity-driven excitatory inputs and excitatory synaptic transmission onto PV interneurons. Neuronal activity-induced ErbB4-PSD-95 association facilitated transsynaptic binding of ErbB4-NRXN1β and excitatory synapse formation in ErbB4-positive interneurons. Furthermore, ErbB4-NRXN1β binding was responsible for the activity-regulated activation of ErbB4 and extracellular signal-regulated kinase (ERK) 1/2 in PV interneurons, as well as synaptic plasticity-related expression of brain-derived neurotrophic factor (BDNF). Correlatedly, blocking ErbB4-NRXN1β coupling in the medial prefrontal cortex of adult mice facilitated reversal learning of an olfactory associative task. These findings provide novel insight into the physiological role of PV interneuron ErbB4 signaling in cognitive processes and reveal an associative learning-related transsynaptic NRXN1β-ErbB4-PSD-95 complex that affects the ERK1/2-BDNF pathway and underlies local inhibitory circuit plasticity and proactive interference.


Human and mouse model cognitive phenotypes in Down syndrome: implications for assessment.
The study of cognitive function in Down syndrome (DS) has advanced rapidly in the past decade. Mouse models have generated data regarding the neurological basis for the specific cognitive profile of DS (i.e., deficits in aspects of hippocampal, prefrontal, and cerebellar function) and have uncovered pharmacological treatments with the potential to affect this phenotype. Given this progress, the field is at a juncture in which we require assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this chapter, we describe the cognitive profile of humans with DS and associated mouse models, discussing the ways in which we may merge these findings so as to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed.


Histological grading of tumour regression and radiation colitis in locally advanced rectal cancer following neoadjuvant therapy: a critical appraisal.
Locally advanced rectal cancer is commonly treated by neoadjuvant therapy and the resultant tumour response can be quantified histologically. This therapy may also induce radiation colitis, which also can be graded. The aim of this study was to assess the grading of tumour regression and of radiation colitis and their relationship to other prognostic parameters. Between 2000 and 2006, 75 patients (23 women; median duration of follow up, 58 months) with rectal cancer were evaluated. Sixty-three had short-course radiotherapy and 12 had long-course radiotherapy. Tumour regression was graded histologically using the three-point Ryan system: patients with grades 1 and 2 were considered as responders and patients with grade 3 were considered as nonresponders. Radiation colitis was graded histologically as mild, moderate or severe, as described previously (J Pathol 2006; 210: P25). Twenty-nine patients were classified as responders and 46 as nonresponders. The former were less likely to be lymph node positive compared with the latter (P=0.001). Tumour response did not correlate with local recurrence. Responders showed a disease-free survival (not overall survival) advantage at 2 and 5 years over nonresponders. Responders showed a higher rate of postoperative abdominal complications. Histological evidence of regression was demonstrated in patients treated with short-course radiotherapy. There was no relationship between radiation colitis grade and abdominal complications. Radiation colitis grade does not correlate with postoperative complications. More abdominal complications occurred in patients receiving long-course radiotherapy.


Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis.
Hypersensitivity pneumonitis (HP) is a lung inflammatory disease caused by the inhalation of a variety of antigens. Previous studies support the role of the major histocompatibility complex (MHC) class II genes in the susceptibility to develop HP. However, the putative role of other MHC loci has not been elucidated. Transporters associated with antigen processing (TAP) genes are located within the MHC class II region and play an important role transporting peptides across the endoplasmic reticulum membrane for MHC class I molecules assembly. The distribution of single nucleotide polymorphisms (SNPs) in TAP1 genes was analyzed in 73 hypersensitivity pneumonitis (HP) patients and 58 normal subjects. We found a significant association of the allele Gly-637 (GGC) (p=0.00004, OR=27.30, CI=3.87-548.04) and the genotypes Asp-637/Gly-637 (p=0.01, OR=16.0, CI=2.19-631.21), Pro-661/Pro-661 (p=0.006, OR=11.30, CI=2.28-75.77) with HP. A significant decrease in the frequency of the allele Pro-661 (CCA) (p=0.008, OR=0.06, CI=0-0.45), the genotype Asp-637/Asp-637 (p=0.01, OR=0.17, 95% CI=0.05-0.58) and the haplotype [Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro-661 (CCA)] was detected in HP patients compared with controls (p=0.002, OR=0.07, CI=0.0-0.57). These findings suggest that TAP1 gene polymorphisms are related to HP risk, and highlight the importance of the MHC in the development of this disease.


Distinct immunohistochemically defined areas in the medial amygdala in the developing and adult mouse.
The medial amygdala has been considered a subpallial structure, but various studies have shown that is a somewhat complex structure expressing both pallial and subpallial gene markers. In this regard, we analyzed the immunohistochemical expression of the neurotransmitter GABA, the vesicular glutamate transporter type 2 (VGLUT2), the neuronal nitric oxide synthase (nNOS), and the calcium-binding proteins calbindin-D28k (CB) and calretinin (CR) in the developing and adult mouse medial amygdala. From intermediate embryonic stages on, neurochemical data show a distinctive superficial region forming a band all along the medial amygdalar surface. This superficial band displays a strong VGLUT2-immunoreactive neuropil and numerous CR-immunoreactive fibers, as well as some nNOS-, CR- or CB-positive cells. In contrast, the superficial region of the posterior medial amygdala appears to be non-GABA immunoreactive. This band in the posterior medial amygdala matches a Tbr1-expressing territory. Our results also show differences between dorsal and ventral parts of the postnatal and adult posterior medial amygdala. Especially, a compact cell aggregate of nNOS immunoreactive cells was found in the ventral portion of the medial amygdala, whereas the dorsal part is occupied by scattered weakly stained cells. Comparison of our results with gene expression patterns and fiber-tracing studies, let us to propose that the superficial band is a pallial derivative, whereas the dorsal and ventral nuclei of the posterior medial amygdala receive each neurons from different subpallial compartments, and the latter one a subset of excitatory, pallial projection neurons.


Hydrogen bond-mediated recognition of the chemical warfare agent soman (GD).
NMR titration studies in acetonitrile-d(3)/DMSO-d(6) mixtures demonstrate that diindolylurea-based receptors can form complexes with the organophosphorus nerve agent soman in organic solution.


Comparison of efficacy of implanted cardioverter-defibrillator in patients with versus without diabetes mellitus.
In the second Multicenter Automatic Defibrillator Implantation Trial, patients with a previous myocardial infarction and left ventricular ejection fraction < or =0.30 benefited significantly from prophylactic implantable cardioverter-defibrillator (ICD) placement. Diabetic patients who had a myocardial infarction had a worse prognosis compared with nondiabetics. The present study used data from the second Multicenter Automatic Defibrillator Implantation Trial to assess the efficacy of ICD placement on survival in diabetic patients. Of the 1,232 patients in the second Multicenter Automatic Defibrillator Implantation Trial, 489 were characterized as diabetic. They were more likely to be New York Heart Association class II to IV, be hypertensive, have renal dysfunction, have an increased body mass index, and to take diuretic drugs. Diabetic patients had a 24% greater adjusted risk of death than nondiabetic patients. The hazard ratio (HR) for the risk of death in patients treated with the ICD compared with conventional therapy was similar in diabetics (HR 0.61; 95% confidence interval [CI] 0.38 to 0.98) and nondiabetics (HR 0.71; 95% CI 0.49 to 1.05), with no evidence of interaction. Thus, diabetic patients derive a similar benefit from ICD therapy despite being sicker and having a higher mortality rate overall.


Nasopharyngeal carriage of Haemophilus influenzae among adults with co-morbidities.
After the widespread use of Haemophilus influenzae type b (Hib) vaccine, H. influenzae invasive disease is now commonly due to non-encapsulated (NTHi), affecting mostly the youngest and the elderly. The objective of this study was to investigate H. influenzae nasopharyngeal carriage rate in adults with co-morbidities and possible associated risk factors. Patients aged >50 years with co-morbidities attending medical centres were examined. A nasopharyngeal swab was analysed for H. influenzae presence by cultural and molecular methods (RT-PCR). Univariable and multivariable analysis of risk factors for H. influenzae carriage were performed. Serotype of isolates was determined by PCR capsular genotyping. Minimum inhibitory concentration (MIC) was determined by MIC gradient test and β-lactamase production was detected by the nitrocephin test. Genotyping was performed by Multilocus sequence typing (MLST). Phylogenetic relationships among carriage and invasive NTHi strains were assessed. Among 248 enrolled patients (median age: 73 years), the carriage rate was 5.6% and 10.5% by cultural method or RT-PCR, respectively. Colonization with H. influenzae was significantly associated with the presence of acute respiratory symptoms (adjusted OR = 12.16, 95% CI: 3.05-48.58, p < 0.001). All colonizing isolates were NTHi. Three isolates (3/14, 21.4%) were resistant to ampicillin and beta-lactamase positive. MLST revealed a high degree of genetic diversity, with 11 different STs from 14 isolates. Eight out of the 11 (72.7%) STs were shared among carriage and invasive isolates. Adults ≥50 years old with co-morbidities are occasionally colonized by H. influenzae, even if the presence of co-morbidities is not a risk factor for colonization. The presence of acute respiratory symptoms is the only factor associated with H. influenzae colonization. Colonizing H. influenzae are all NTHi. Colonizing H. influenzae often belong to the same STs of invasive disease isolates.


Release of Extra Articular Ankylosis of Jaws as a Sequelae of Cancrum Oris with Extensive Gingival Myasis in a Scoliosis Patient: A Rare Case Report.
'Noma' is an allusion to the rapidly destructive course of gangrene (Emmanuel et al. in J Maxillofac Surg 11:160-170, 1983). The pathogenicity is related to the high bacterial load of microorganisms resulting in gangrene that rapidly invades the facial tissues. The infection causes perforating wounds of the lips, cheek, nose, palate and bony fusion of the maxilla and mandible.


Calculation of the laser diffraction intensity of striated muscle by numerical methods.
The diffraction of a laser beam by striated muscle was treated as Fraunhofer diffraction of a homogeneous system. Assuming that the striated muscle was a three-dimensional array of cylindrical sarcomeres, a set of diffraction equations in cylindrical reciprocal coordinates for calculating the diffraction intensity as a function of the polar and azimuthal angles was derived. After the positions and dimensions of the sarcomeres were specified, numerical calculations according to the diffraction equations yielded the intensity pattern on both the meridional and equatorial planes. As a sample calculation for the diffraction intensity, the sarcomere positions and dimensions derived from light microscopy and light diffractometry on living muscle fibers were used. The calculated diffraction intensity pattern of a skeletal muscle fiber correlated well with experimental measurements.