Are high-pass resolution perimetry thresholds sampling limited or optically limited?

PURPOSE: It has been reported that high-pass resolution perimetry (HRP) provides a means of noninvasively determining retinal ganglion cell density. However, there is evidence to suggest that this may not be true. The purpose of the present study was to determine whether HRP thresholds are sampling limited, which is a necessary condition for being able to determine retinal ganglion cell density psychophysically. METHODS: This study measured resolution and detection performance for a range of grating-based stimuli under the testing conditions that HRP uses and compared these with performance of the ring stimulus. RESULTS: The results show that detection and resolution acuity under HRP test conditions were often equivalent, in accordance with previous investigations. However, the results also show that the thresholds underestimated the true level of resolution acuity in the periphery because increasing stimulus contrast increased performance. CONCLUSION: These findings suggest that HRP thresholds cannot be regarded as sampling limited, but rather they are optically limited. We therefore conclude that HRP thresholds cannot be regarded as a direct measure of the underlying ganglion cell density.     

Peripheral arteriovenous malformation: diagnosis and localization by intraarterial injection of technetium-99m-MAA

Radionuclide angiography with technetium-99m-labeled macroaggregates of albumin (99mTc-MAA), was successful in a single patient with a lower limb arteriovenous (AV) malformation, not only in diagnosis and quantitation of AV shunting, but also in localizing the site of shunting. This information proved useful to the angiographer, permitting a carefully tailored examination of the area of interest. This technique may hold promise as a preliminary examination in patients with limb AV malformations prior to angiography.     

Primary Ewing sarcoma: follow-up with Ga-67 scintigraphy

While avid accumulation of gallium-67 citrate and technetium-99m methylene diphosphonate (MDP) occurs initially in most cases of primary Ewing sarcoma, uptake after therapy is less well defined. Thirty patients with Ewing sarcoma who underwent Ga-67 and bone scintigraphy at diagnosis, at completion of therapy, and at relapse from 1978 to 1988 were evaluated. All 30 patients showed less primary site Ga-67 activity following therapy. Twenty-three of 28 patients who underwent corresponding bone scintigraphy showed less uptake, but residual activity was usually more intense than with Ga-67. Avid reaccumulation of Ga-67 occurred in four of five patients with primary site relapse, while patients who underwent bone scintigraphy showed less change. It was concluded that a greater decrease in Ga-67 than in Tc-99m MDP uptake often occurs in patients successfully treated for primary Ewing sarcoma. Information obtained at Ga-67 scintigraphy is most likely to be helpful if results of bone scintigraphy remain abnormal or if occult relapse is suspected.     

脾切除对结直肠癌切除术后的影响：一项多中心、嵌入式、配对队列研究

目的探讨医源性脾脏损伤脾切除对结直肠癌切除患者术后长期生存的影响。方法对1990年1月1日至1999年12月31日10年间行结直肠癌手术切除并附带脾切除患者进行病例配对回顾研究。分析患者年龄、性别、依据美国麻醉学医师协会（ASA）标准评估的身体状况、疾病分期、手术类型及预后等资料。配对病例来自同一医疗中心，性别、年龄、疾病分期及手术类型完全相同。手术附带脾切除患者为试验组，未切脾者为对照组。结果55例患者行医源性脾切除术，对照组在年龄、性别、身体状况、疾病分期及手术类型上与之匹配。随访时间（从手术开始到患者死亡或者最后一次随访1为2～205个月（中位随访时间为43个月）。Cox比例危险度模型进行Kaplan-Meier法生存分析发现两组间差异有显著性意义，不切除脾脏对患者生存有利（危险度1．8，95％可信区间为1-3．3，P=0．0399），未切脾组与切脾组5年生存率分别为70％和47％，10年生存率分别为55％和38％。结论结直肠癌患者在行结肠或直肠切除时，因医源性脾脏损伤而切除脾脏者，预后较差。     

Adenosine, mast cells and asthma

The aim of this article is to review the interplay between adenosine and mast cells in asthma. Adenosine is an endogenous nucleoside released from metabolically active cells and generated extracellularly via the degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types including platelets, neutrophils and mast cells via action at specific adenosine receptors (A1, A2a, A2b, A3). These receptors are expressed on mast cells but the exact pattern of receptor subtype expression depends on the source of the mast cells. Adenosine is also a potent bronchoconstricting agent and is suggested to contribute to the pathophysiology of asthma. Evidence is provided to suggest that the nucleoside exerts its influence on the asthmatic condition through its ability to modulate the release of mast cell derived mediators. However, the mechanism of adenosine/mast cell interaction which contributes to asthma remains unclear. Progress in the area has been hampered by the heterogeneity of mast cell responses and a lack of highly specific receptor agonists and antagonists. The expression of different adenosine receptor subtypes on mast cells is described. The final section of the review presents data to suggest that BAL mast cells may provide an accurate and relevant model for future investigations and together with the development of superior pharmacological tools, may aid the realisation of the therapeutic potential of adenosine/mast cell interactions in asthma. In conclusion, the role of adenosine in asthma is clearly complex. A better understanding of the contribution of adenosine to the asthmatic condition may lead to novel therapeutic approaches in the treatment of the disease.     

Modulation of histamine release from rat peritoneal mast cells by non-cytotoxic concentrations of the detergents Cremophor El (oxethylated castor oil) and Triton X100. A possible explanation for unexpected adverse drug reactions?

Clinically relevant histamine release caused by drugs and/or their solvents is a well known phenomenon. The mechanisms whereby these reactions occur are largely unknown. It was thought that the solubilizing agents potentiate the histamine release elicited by the drugs. Therefore the ability of the two detergents, Cremophor El and Triton X100, to modulate histamine release from rat peritoneal mast cells was examined. Both detergents were used in concentrations that did not themselves induce histamine release. The addition of the detergents to incubation media containing compound 48/80 (0.1 microgram/ml) elevated the release considerably (48/80 alone = 16.2 +/- 2.1% (n = 3); plus Cremophor El (5%) = 41.1 +/- 3.3% (n = 4); plus Triton X100 (0.02 microliter/ml) = 39.7 +/- 3.9% (n = 3); plus Triton X100 (0.01 microliter/ml) = 33.4 +/- 5.0% (n = 3)). In contrast, histamine release induced by Concanavalin A or the calcium ionophore A 23187 was inhibited by both detergents. Thus low concentrations of detergents appear to have a dual role, with both potentiation and inhibition of histamine release being observed. Surgical patients receive many drugs, some soluble in aqueous solutions, others only with the aid of solubilizing agents. 'Hangover effects' due to different plasma half lives, may therefore cause a seemingly harmless drug to act as a histamine liberator. It is therefore important to examine the action of clinically used solvents on histamine liberation caused by therapeutic agents, in order to gain a further understanding of the reaction mechanisms of adverse reactions to drugs.     

A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes

PurposeExome and genome sequencing have drastically accelerated novel disease gene discoveries. However, discovery is still hindered by myriad variants of uncertain significance found in genes of undetermined biological function. This necessitates intensive functional experiments on genes of equal predicted causality, leading to a major bottleneck.MethodsWe apply the loss-of-function observed/expected upper-bound fraction metric of intolerance to gene inactivation to curate a list of predicted haploinsufficient disease genes. Using data from the 100,000 Genomes Project, we adopt a gene-to-patient approach that matches de novo loss-of-function variants in constrained genes to patients with rare disease. Through large-scale aggregation of data, we reduce excess analytical noise currently hindering novel discoveries.ResultsResults from 13,949 trios revealed 643 rare, de novo predicted loss-of-function events filtered from 1044 loss-of-function observed/expected upper-bound fraction–constrained genes. A total of 168 variants occurred within 126 genes without a known disease-gene relationship. Of these, 27 genes had >1 kindred affected, and for 18 of these genes, multiple kindreds had overlapping phenotypes. Two years after initial analysis, 11 of 18 (61%) of these genes have been independently published as novel disease gene discoveries.ConclusionUsing large cohorts and adopting gene-based approaches can rapidly and objectively accelerate dominantly inherited novel gene discovery by targeting the most appropriate genes for functional validation.     

Characterization of basal and re-inflammation-associated long-term alteration in pain responsivity following short-lasting neonatal local inflammatory insult

Recently, several studies have suggested that neonatal noxious insult could alter future responses to painful stimuli. However, the manifestations, mechanisms, and even developmental nature of these alterations remain a matter of controversy. In part, this is due to the lack of detailed information on the neonatal sensitive period(s) during which noxious stimulation influences future nociception, and the time-course and distribution of the resultant abnormalities. The present paper describes these parameters in a rat model of short-lasting (24 h) neonatal local inflammation of a hindpaw produced by injection of 0.25% carrageenan (1 μl/g). Examinations of paw withdrawal responses to thermal and mechanical stimulations in adult animals, which as neonates were subjected to this insult, showed that the previously-reported long-term hypoalgesia and hyperalgesia are not mutually exclusive outcomes of early noxious experience. Long-term hypoalgesia was apparent at the basal conditions and was equally strong in the previously injured and uninjured paws, which suggests a globally-driven deficit. In contrast, long-term excessive hyperalgesia had the strongest manifestation in the neonatally-injured paw after re-inflammation, indicating significant segmental involvement in its generation. The differences between mechanisms underlying the observed hypoalgesia and hyperalgesia are further underscored by the finding that, while the former is detectable only after animals reach the second month of life, the latter is elicitable immediately upon cessation of the initial neonatal inflammation. Nevertheless, we detected a significant overlap in the neonatal sensitive periods for generation of these effects (both occurring within the first postnatal week). Also, neither the basal hypoalgesia nor excessive re-inflammation-associated hyperalgesia subsided with age and were detectable in 120–125-day-old rats. These finding provide a framework within which the entire complex of long-term effects of early noxious experience can be understood and examined.     

Precut papillotomy versus persistence in difficult biliary cannulation: a prospective randomized trial

BACKGROUND AND STUDY AIMS: Failed biliary cannulation occurs in up to 10% of patients undergoing ERCP. There is some controversy as to the safety and efficacy of using precut techniques to achieve biliary cannulation in difficult cases. To date, no randomized trial has compared the success and complication rates of precut with the rates for persistence when biliary cannulation is difficult. The aim of this study was to compare the success rates and complication rates of precut with the success rates and complication rates of persistence in cases of difficult biliary cannulation. PATIENTS AND METHODS: Patients without prior sphincterotomy who required biliary cannulation were screened. A "difficult biliary cannulation" was arbitrarily defined as failed cannulation after 12 minutes. These patients were then randomized to continue treatment by needle-knife cut over the roof of the papilla or by persistence with a non-wire-guided, single-lumen papillotome. "Primary" success was defined as deep cannulation within 15 minutes of randomization. Primary and final success rates and complication rates within 30 days after ERCP were compared. RESULTS: Over a 38-month period a total of 642 patients were screened. Patients in whom biliary cannulation was successful within a time period of 12 minutes or less formed the reference group (n = 580). The remainder of the patients were randomly assigned to the "precut" arm (n = 32) or to the "persistence" arm (n = 30). Primary success rates and complication rates were similar in the precut and persistence arms (75% and 4% respectively for the precut arm vs. 73% and 9% for the persistence arm). The final successful cannulation rate in the entire group of 642 patients was 99.5%. CONCLUSIONS: In experienced hands, precut papillotomy and persistence in cannulation are equally effective in cases of difficult cannulation, with a similar complication rate.