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Invasive plant pathogenic fungi have a global impact, with devastating economic and environmental effects on crops and forests. Biosurveillance, a critical component of threat mitigation, requires risk prediction based on fungal lifestyles and traits. Recent studies have revealed distinct genomic patterns associated with specific groups of plant pathogenic fungi. We sought to establish whether these phytopathogenic genomic patterns hold across diverse taxonomic and ecological groups from the Ascomycota and Basidiomycota, and furthermore, if those patterns can be used in a predictive capacity for biosurveillance. Using a supervised machine learning approach that integrates phylogenetic and genomic data, we analyzed 387 fungal genomes to test a proof-of-concept for the use of genomic signatures in predicting fungal phytopathogenic lifestyles and traits during biosurveillance activities. Our machine learning feature sets were derived from genome annotation data of carbohydrate-active enzymes (CAZymes), peptidases, secondary metabolite clusters (SMCs), transporters, and transcription factors. We found that machine learning could successfully predict fungal lifestyles and traits across taxonomic groups, with the best predictive performance coming from feature sets comprising CAZyme, peptidase, and SMC data. While phylogeny was an important component in most predictions, the inclusion of genomic data improved prediction performance for every lifestyle and trait tested. Plant pathogenicity was one of the best-predicted traits, showing the promise of predictive genomics for biosurveillance applications. Furthermore, our machine learning approach revealed expansions in the number of genes from specific CAZyme and peptidase families in the genomes of plant pathogens compared to non-phytopathogenic genomes (saprotrophs, endo- and ectomycorrhizal fungi). Such genomic feature profiles give insight into the evolution of fungal phytopathogenicity and could be useful to predict the risks of unknown fungi in future biosurveillance activities., (© 2023. Springer Nature Limited.)

BCL-2 family proteins are frequently aberrantly expressed in mantle cell lymphoma (MCL). Recently, the BCL-2-specific inhibitor venetoclax has been approved by the US Food and Drug Administration for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In MCL, venetoclax has shown promising efficacy in early clinical trials; however, a significant subset of patients is resistant. By conducting a kinome-centered CRISPR-Cas9 knockout sensitizer screen, we identified casein kinase 2 (CK2) as a major regulator of venetoclax resistance in MCL. Interestingly, CK2 is over-expressed in MCL and high CK2 expression is associated with poor patient survival. Targeting of CK2, either by inducible short hairpin RNA (shRNA)-mediated knockdown of CK2 or by the CK2-inhibitor silmitasertib, did not affect cell viability by itself, but strongly synergized with venetoclax in both MCL cell lines and primary samples, also if combined with ibrutinib. Furthermore, targeting of CK2 reduced MCL-1 levels, which involved impaired MCL-1 translation by inhibition of eIF4F complex assembly, without affecting BCL-2 and BCL-XL expression. Combined, this results in enhanced BCL-2 dependence and, consequently, venetoclax sensitization. In cocultures, targeting of CK2 overcame stroma-mediated venetoclax resistance of MCL cells. Taken together, our findings indicate that targeting of CK2 sensitizes MCL cells to venetoclax through downregulation of MCL-1. These novel insights provide a strong rationale for combining venetoclax with CK2 inhibition as therapeutic strategy for MCL patients.

Mature B-cell lymphomas are highly dependent upon the protective lymphoid organ microenvironment for their growth and survival. Targeting integrin-mediated homing and retention of the malignant B cells in the lymphoid organs, using the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, is a highly efficacious FDA-approved therapy for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). Unfortunately, a significant subset of patients is intrinsically resistant to ibrutinib or will develop resistance upon prolonged treatment. Here, we describe an unbiased functional genomic CRISPR-Cas9 screening method to identify novel proteins involved in B-cell receptor-controlled integrin-mediated adhesion, which provides novel therapeutic targets to overcome ibrutinib resistance. This screening method is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types. Graphical abstract., Competing Interests: Competing interests The authors have no competing interests to declare., (Copyright © 2022 The Authors; exclusive licensee Bio-protocol LLC.)

The clinical introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types., (© 2022. The Author(s).)

Purpose: To compare the safety and efficacy of RIRS in patients ≥ 80 years to a younger population., Methods: We retrospectively compared the data from patients ≥ 80 years of age undergoing RIRS with the data of a group of patients from 18 and < 80 years. Perioperative outcomes, complications and emergency department visits were compared between two groups., Results: A total of 173 patients were included in the study. Mean age was 44 (27-79) and 81 years-old (80-94), for younger and elderly group, respectively. Elderly patients had higher ASA scores (≥ 3) (28.6% vs 75.8%; p = 0.0001) and Charlson comorbidity index (1.99 vs 7.86; p = 0.0001), more diabetes (p = 0.006) and respiratory comorbidities (p = 0.002). No statistical difference was found between two groups in stone size (p = 0.614) and number (p = 0.152). Operative time (74.48 vs 102.96 min; p = 0.0001) and duration of hospitalisation (1.7 vs 2.9 days; p = 0.001) were longer for the elderly. Intraoperative complication rate did not show differences between the two groups (p = 0.166). Postoperative complications rates were similar between the cohorts (7.7% vs 9.5%; p = 0.682). The success rates were 67.5% in the younger group and 71.4% in the elderly group (p = 0.584). No difference was seen in stone recurrence (p = 0.73). A higher rate of visits to the emergency department was found in younger cohort (23.6% vs 11.6%; p = 0.046), mostly duo to stent-related symptoms., Conclusions: Despite the higher rate of comorbidity in the elderly group, RIRS was a safe procedure with similar complication rate and outcomes at an expense of higher operative time and hospital stay., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy.

Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.

Background: Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma., Design and Methods: Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation., Results: The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis., Conclusions: Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

The renal cancer (RC) cystic component is on the radiological tests and could be consolidate with pathological analysis. The concepts "cystic renal cancer" or "cystic renal tumor" contain a group of entities range from cystic grown pattern RCs to pseudocystic tumors as well as cystic renal diseases coinciding with the RC. The CR and the cystic renal diseases have a great variety to sorts of presentations, giving different ways of radiological images, blending solid and cystic areas. Some papers use indiscriminately expression "cystic" without pathologic proof. Just cystic grown pattern RCs and multilocular cystic carcinoma could be named "cystic renal tumors". For de rest, especially over image study, is more suitable to use expressions as "renal tumor of cystic configuration", while pathologic report are available.

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.

Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.

Primary sclerosing cholangitis is a condition of unknown cause. It is recognized by liver dysfunction and its characteristic radiologic appearance, which is related to portal tract inflammation, bile duct proliferation, and periductal fibroses involving small intrahepatic and large extrahepatic ducts. The disease lasts about 10 years from the time of diagnosis. Primary sclerosing cholangitis is recognized by abnormal results on routine liver function tests or by the development of clinical jaundice. An autoimmune cause has been suggested because of its strong association with inflammatory bowel disease, certain antigens, AIDS, and immunoregulatory abnormalities. Results of medical management of sclerosing cholangitis have been disappointing. Immunosuppressive drugs, copper chelating agents, and antibiotics have failed to alter progression of the disease. Colectomy in patients with inflammatory bowel disease also has no influence. The judicious use of dilations of strictures, bypass procedures, or resection can palliate jaundice in patients with primary sclerosing cholangitis, but liver transplantation is the definitive treatment. Because palliative operations increase the hazards of liver transplantation, percutaneous dilations and stentings are preferred initially. Cirrhosis and portal hypertension are indications for transplantation. In the future, transplantation may be indicated earlier in the course of the disease.

Of 178 patients with sclerosing cholangitis treated since 1950, 88 patients had associated inflammatory bowel disease, 72 had no such history, and 18 had iatrogenic injury or stone disease. A total of 233 biliary operations were performed, with a 75% rate of temporary improvement after initial operation. Subsequent operations resulted in a lower success rate and a higher mortality rate. Radiologic findings included predominant extrahepatic, intrahepatic, and diffuse disease in 29%, 28%, and 43% of patients, respectively; no survival differences were noted. Seventy-five of one hundred three deaths (73%) were related to liver failure, bleeding, or sepsis. Of 14 patients undergoing portosystemic shunt, 13 died of surgical complications or related disease. Orthotopic liver transplantation was performed in 16 patients and resulted in eight deaths, mainly in patients who had previously undergone extensive surgical treatment. No survival differences were seen between the patients with inflammatory bowel disease, those without the condition, or those who had colectomy. Surgical treatment in patients with sclerosing cholangitis should be minimized. Orthotopic liver transplantation should be offered as the treatment of choice for patients with portal hypertension, refractory cholangitis, advanced cirrhosis, or progressive liver failure.

The authors reviewed their experience with 12 patients (median age, 38 years; range, 24 to 66 years) who had bleeding stomal varices. Stomal variceal bleeding occurred between 1 and 11 years (median, 5.5 years) after creation of the stoma. Control of bleeding initially consisted of direct pressure; recurrent bleeding occurred in one patient who died before definitive therapy could be performed. The remaining 11 patients underwent a total of 18 additional procedures for control of bleeding stomal varices, including 9 local procedures, 8 portosystemic shunts, and 1 liver transplantation. Seven patients were dead of hepatic failure a median of 4 years (range, 1 to 9 years) after treatment. Recurrent bleeding occurred in three patients after local treatment and in one patient after a portosystemic shunt. Bleeding stomal varices are a manifestation of severe liver disease and portal hypertension. Although local procedures may be effective for initial control of bleeding, recurrent bleeding often occurs. Mortality is high because of the severity of the underlying liver disease.

Perioperative data on 87 patients undergoing pancreatoduodenectomy for periampullary tumors were correlated with pathologic study of operative specimens to identify the accuracy of diagnosis and the factors affecting survival. Accuracy of endoscopic retrograde cholangiopancreatography and computed tomography in locating lesions was 75% and 44%, respectively. Histologic diagnosis before or at the time of resection was available in only 61% of the patients. Carcinoma was correctly diagnosed clinically by the pathologist or the surgeon in 95% (83/87) of patients with 4 patients found to have benign disease on final pathologic examination. Intraoperative diagnosis of site of origin was incorrect in 18% (16/87) of patients. In 28% (23/83) of patients, pathologists identified nodal metastatic disease missed by the surgeon. Survival correlated with nodal and margin status and tumor grade. Tumor size demonstrated no predictive capacity. Although preoperative diagnostic accuracy is less than optimal, surgeons can usually diagnose malignant lesions but more often fail to identify tumor origin and nodal disease. We continue to advocate resection for patients with periampullary lesions thought to be malignant and resectable without a positive histologic diagnosis.

In a study of a representative sample of 301 "children's hearings", particular attention was given to 27 cases in which the child was committed to a List D school. Because the Scottish juvenile justice system has an explicit commitment to promoting the welfare of the children with whom it deals, the decisions were examined with special reference to the objectives that the hearing members hoped to achieve. These decisions could be divided into: (1) those which reflected only a sense that all alternatives had been exhausted; (2) those which aimed to ensure that the child received formal education or was placed in an environment which would help resolve his personal difficulties; (3) those designed to protect the child from family stresses or to achieve some other specific purpose. Since decisions under (1) are incompatible with the formal philosophy of the system, most of those under (2) entail no knowledge of the effectiveness of List D schools for the purposes in question, and some of those under (3) were wholly misconceived, it is concluded that there are some significant inconsistencies between the system's ideology and the actual practice of its members.

In this study, we compared responses to norepinephrine (NE) by thoracic aortic rings isolated from rats made septic by cecal ligation with puncture, and aortic tissue from sham-operated control rats. We also examined the responses of septic and sham-operated rat aortas after removal of the vascular endothelium. Acetylcholine caused relaxation of NE-induced contractions in septic and sham tissue with an intact endothelium but had no effect on tissue with the endothelium removed experimentally. In preparations with intact endothelium, septic tissue manifests a significantly diminished maximal contractile response to NE (424 +/- 62 (SE) mg tension/mg tissue) in comparison to sham tissue (747 + 30). Tissues with the endothelium removed show no significant maximal contractile difference between septic (688 +/- 23) and sham (669 +/- 32) preparations, or the equivalent sham tissue with an intact endothelium. No difference in the log ED50 for sham tissue (-7.33 +/- 0.12 M) and septic tissue (-7.53 +/- 0.15) with intact endothelium existed. Removal of the endothelium from both septic and sham tissue shifted the dose response curves to the left, disclosing a significant difference in the ED50 between sham (-8.88 +/- 0.14) and septic (-8.18 +/- 0.20) tissue. In conclusion, a significant impairment of vascular contractility in response to NE, with no change in ED50, persists in septic vascular tissue in vitro, and the sepsis-induced defect in contractility is mediated, at least in part, by vascular endothelium, since removal of the endothelium partially restores the NE-stimulated contraction to normal.

The effects of exposure to CdCl2 aerosols followed by hyperoxia were studied in mouse lung. Special emphasis was placed on analysis of cell proliferation following injury. Male Balb/c mice were exposed to aerosols of 4.9 micrograms Cd/liter for 1 hr while controls were exposed to water aerosols. Immediately after, half of each group was placed in 80% O2 for 6 days, while the rest were left in room air. Three endpoints were used to assess lung injury; measurement of hydroxyproline, [14C]thymidine incorporation into DNA, and histopathology. Parenchymal and bronchiolar labeling indices were determined following autoradiography. A 1-hr exposure to CdCl2 aerosols caused marked cell proliferation in the lung with the peak of cell labeling occurring at Day 5. In animals exposed to both CdCl2 + 80% O2, the cell labeling peak was delayed until Day 9. Cell differentiation studies showed a delay in the peak of type II epithelial cell and endothelial cell division when CdCl2 exposure was followed by the 80% O2 treatment. On Day 15 most of the labeled cells were identified as interstitial cells in both treated groups. Bronchiolar cell labeling was suppressed at the early time period in the Cd + O2 group. With time, the histologically visible lung lesions tended to resolve in animals exposed to CdCl2 or CdCl2 and 80% O2, whereas total pulmonary hydroxyproline remained at all times (3, 6, and 12 months) significantly higher in Cd-treated animals when compared to controls. It was concluded that acute lung injury by a toxic inhalant can be amplified if there is an initial delay in pulmonary cell proliferation following an acute insult.

A case is described that represents the only reported patient with glucagonoma syndrome and morbid obesity. The diagnosis of glucagonoma should be considered in any patient with the classic criteria despite weight gain. The criteria for diagnosis of glucagonoma are 1) the presence of a glucagon-secreting tumor, 2) hyperglucagonemia, and 3) the clinical manifestations of either necrolytic migratory erythema, glucose intolerance, or hypoaminoacidemia.

The intraperitoneal administration of methylcyclopentadienyl manganese tricarbonyl (MMT) and cyclophosphamide, exposure to an aerosol of cadmium chloride, intravenous administration of oleic acid, and intratracheal instillation of bleomycin to young female BALB/c mice or CD/CR rats result in acute lung injury. Pulmonary morphology and lung collagen content were examined in animals treated with these chemicals alone or in combination with an elevated oxygen concentration (80%) in the inspired air. In mice, the development of fibrosis could be significantly enhanced if animals treated with MMT, cadmium chloride, cyclophosphamide, or bleomycin were exposed to 80% oxygen immediately following exposure to these agents. In rats only cyclophosphamide- and bleomycin-induced acute lung injury was potentiated by hyperoxia, resulting in significant enhancement of lung collagen content. The pathogenesis responsible for this differential species response of pulmonary injury to hyperoxia remains to be investigated.

The cause of liver abscess is frequently obscure at initial presentation. We reviewed the medical records of 20 patients with pyogenic liver abscess over a 6-year period from 1981 to 1987. Liver abscess was suspected in only 3 patients on admission; the most common initial diagnosis was fever of unknown origin. Subsequently, the origin of the abscess was found to be intestinal in 7 patients, pancreatobiliary in 11 patients, and cryptogenic in 2 patients. Eleven patients underwent percutaneous transhepatic drainage of the abscess as the initial treatment, while open operation was the initial treatment in 9 patients. Percutaneous transhepatic drainage was ultimately successful in only 4 patients (36%). In the absence of an obvious pathologic condition of the biliary tract, all patients should undergo full gastrointestinal evaluation.

1. The classification of adenosine receptor subtypes (A1 and A2) in intact tissues has been based on the order of agonist potency. In this study the apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine (CPX), an antagonist which has been reported to be A1 selective, and the non-selective antagonist 1,3-dimethyl-8-phenylxanthine (8PT) has been evaluated on isolated tissues from the guinea-pig. 2. The isolated tissues used were atria (bradycardic response, proposed A1 sub-type), aorta and trachea (relaxant response, proposed A2 sub-type). 3. Both the xanthines antagonized responses to adenosine in the three tissues but had little or no effect on responses to carbachol (atria), sodium nitrite (aorta) or isoprenaline (trachea). 4. pA2 values for 8PT were similar on the three tissues (6.3-6.7), however, the pA2 value for CPX on the atria (7.9-8.4) was greater than that on the aorta (6.6) or trachea (6.6). 5. These results support the suggestion that the adenosine receptors which mediate bradycardia in the atrium are of the A1 sub-type and that those which mediate relaxation in the aorta and trachea are of the A2 type.

Conservative management of pancreatic fistulas resulting from trauma, operation for tumor, or operation for pancreatitis has met with variable success. To assess optimal management strategies and outcome, we reviewed the records of 35 patients with external pancreatic fistulas (26 patients), pancreatic ascites (6 patients), or pancreatic pleural effusion (3 patients). Treatment included no operation in 5 patients, oversewing of the fistula in 7 patients, internal drainage in 11 patients, and resection in 12 patients. One (3%) postoperative death occurred. The overall rate of operative success was 83% (25 patients). The incidence of recurrent fistulas was about the same regardless of the procedure. Patients treated successfully without operation did not have pancreatitis as an underlying disease. Patient selection is of great importance in the decision to resect or to drain and is based in part on imaging the pancreatic duct and fistula.

Colonic pseudo-obstruction has been recognized since Ogilvie described this disease in 1948. Metabolic, surgical, and medical causes have been implicated at various times. Treatment has included surgical decompression by cecostomy and colectomy. Successful nonoperative decompression by colonoscopy was first reported by Kukora and Dent in 1977. Since that report several authors have reported their results using this technique. Presented here is a series of nine patients with colonic pseudo-obstruction treated initially with colonoscopy. Patients presented with a variety of associated conditions, including post operative patients, orthopedic injuries, metastatic carcinoma, and an unusual case after a normal vaginal delivery. Eight patients responded well to colonoscopic decompression. One patient, the second in the series, was unable to be decompressed with colonoscopy and underwent a cecostomy under local anesthesia. Successive colonoscopy may be required to allow restoration of normal colonic function, as was the case in seven of our patients. One death occurred, due to unrelated causes. The authors have found colonoscopy to be a safe and reliable therapy for colonic pseudo-obstruction.

The juvenile justice system established in Scotland in 1971, in which lay volunteers play a central part, provides a framework for making decisions about children in need of care and protection as well as those who have committed delinquent acts. Although cases of child abuse and neglect have come increasingly to the attention of children's hearings in recent years, they nevertheless constitute a small fraction of a workload dominated by cases of delinquency and truancy. A recent Scotland-wide study of the hearings system therefore gave only limited attention to the processing of abuse and neglect referrals. As a step towards rectifying this imbalance, a separate enquiry was carried out in 1981, when 43 such hearings were systematically observed and the participating panel members interviewed. Examination of these results indicates a heavy dependence on social workers' recommendations, a reluctance to open up sensitive areas for discussion, even though these may be of central importance, and an apparent lack of curiosity about the arrangements made for children removed from their homes, and the implications of these. In general, it is concluded that the anxiety generated by child abuse and neglect has prevented panel members from recognizing the distinctive features of their role in the decision-making process and has led them to fall back on an inappropriate model of practice derived from delinquency hearings. An alternative model is outlined.