Inhibition of dipeptidyl peptidase IV (DP IV, CD26) activity abrogates stress-induced, cytokine-mediated murine abortions

In the CBA x DBA/2 mouse model, stress-triggered abortions are mediated by a Th1-like cytokine response of decidual lymphocytes. The factors that determine the cytokine pattern leading to abortion are currently unknown. Dipeptidyl Peptidase IV (DP IV) enhances Th1-cytokine responses and impairs the evolvement of a Th2 cytokine profile. The T-cell-activation antigen, CD26, possesses DP IV activity. The aim of the present study was to investigate the role of DP IV activity and CD26-positive decidual lymphocytes in murine stress-triggered abortions by inhibition of DP IV activity. DBA/2-mated CBA mice were stressed on day 5.5 of pregnancy and received daily injections of an inhibitor of DP IV activity, Ile-thiazolidide (20 micromol/kg). On day 13 of gestation, the animals were sacrificed and the percentage of implants and abortions documented. CD26-positive lymphocytes in spleen and uterine decidua and the intracellular cytokines interferon (IFN)-gamma and interleukin (IL)-10 were determined by flow cytometry. Stressed and nonstressed animals receiving an inactive stereoisomeric form were used as controls. In mice receiving the DP IV inhibitor, stress failed to boost the abortion rate (37.2% versus 13.6%, P < 0.01). IFN-gamma producing cells were increased in stressed animals, but returned to the baseline upon the inhibition of DP IV. The number of IL-10 producing cells was reduced in stressed animals, independent from DP IV inhibition.     

Improving the delivery of palliative care through predictive modeling and healthcare informatics

ObjectiveAccess to palliative care (PC) is important for many patients with uncontrolled symptom burden from serious or complex illness. However, many patients who could benefit from PC do not receive it early enough or at all. We sought to address this problem by building a predictive model into a comprehensive clinical framework with the aims to (i) identify in-hospital patients likely to benefit from a PC consult, and (ii) intervene on such patients by contacting their care team.Materials and MethodsElectronic health record data for 68 349 inpatient encounters in 2017 at a large hospital were used to train a model to predict the need for PC consult. This model was published as a web service, connected to institutional data pipelines, and consumed by a downstream display application monitored by the PC team. For those patients that the PC team deems appropriate, a team member then contacts the patient’s corresponding care team.ResultsTraining performance AUC based on a 20% holdout validation set was 0.90. The most influential variables were previous palliative care, hospital unit, Albumin, Troponin, and metastatic cancer. The model has been successfully integrated into the clinical workflow making real-time predictions on hundreds of patients per day. The model had an “in-production” AUC of 0.91. A clinical trial is currently underway to assess the effect on clinical outcomes.ConclusionsA machine learning model can effectively predict the need for an inpatient PC consult and has been successfully integrated into practice to refer new patients to PC.     

Comparison of Streptococcus mutans and Streptococcus sanguis receptors for human salivary agglutinin.

Oral streptococci vary in their susceptibility to salivary agglutinin-mediated aggregation. To understand the molecular basis of this specificity, the structure and function of receptors for agglutinin from Streptococcus mutans KPSK2 (MSL-1) and Streptococcus sanguis M5 (SSP-5) were compared. Immunological screening of an S. mutans KPSK2 genomic DNA library yielded two identical clones expressing a streptococcal protein that co-migrated with a 220 kDa peptide in SDS extracts from this organism. This protein inhibited agglutinin-mediated aggregation of S. mutans KPSK2 in a dose-dependent manner. The MSL-1 gene is homologous to the S. mutans SpaP and pac genes although single base substitutions alter several amino acids. MSL-1 is also similar to the agglutinin receptor (SSP-5) cloned from S. sanguis M5. All three proteins, MSL-1, P1, and SSP-5 share at least one epitope since monoclonal and polyclonal anti-SSP-5 antibodies react with both MSL-1 and P1. However, other monoclonal antibodies are specific for SSP-5 and appear to react with a peptide domain exhibiting little homology to MSL-1 or P1. Sugar inhibition studies showed that agglutinin-mediated aggregation of S. mutans KPSK2 was most potently inhibited by fucose and lactose. Sialic acid, a potent inhibitor of S. sanguis aggregation, had no effect on the interaction of agglutinin with S. mutans KPSK2. These results suggest that while the MSL-1 and SSP-5 proteins are genetically and immunologically related, their specificity for binding sites on agglutinin differs.     

Chondrex (YKL-40), a potential new serum fibrosis marker in patients with alcoholic liver disease

OBJECTIVES: Chondrex (YKL-40) is a mammalian member of a protein family that includes bacterial chitinases. The pattern of its expression in certain tissues such as human liver or cartilage suggests a function in remodelling or degradation of extracellular matrix. The purpose of this study was to assess whether circulating YKL-40 might be a serum fibrosis marker in alcoholics. METHODS: Plasma YKL-40 was determined in 146 consecutive heavy drinkers (106 men, 40 women; mean age, 49.2 +/- 9.0 years). Liver biochemical parameters and serum fibrosis markers such as hyaluronate were also measured. Fibrosis and inflammation in liver biopsy were evaluated using a semi-quantitative scoring system. RESULTS: Plasma YKL-40 increased in parallel with the severity of fibrosis (P<0.00001). YKL-40 also increased in the presence of hepatic inflammation (P<0.01). Receiver operating characteristic curves of Chondrex revealed that a threshold of 330 microg/l gave a specificity of 88.5%; however, the sensitivity was only 50.8%. Only 11.5% of patients without severe fibrosis displayed a Chondrex plasma level above this threshold. A positive correlation was found between Chondrex and hyaluronate (r=0.40, P<0.0001), and a negative correlation was shown between Chondrex and the prothrombin index (r=-0.37, P<0.0001). CONCLUSIONS: The severity of liver fibrosis is associated with elevated circulating Chondrex levels. The overlap in YKL-40 values prevents use of Chondrex in a screening programme. High levels of Chondrex (above 330 microg/l) are predictive of severe liver fibrosis. Increased plasma YKL-40 may reflect the remodelling of liver fibrosis in alcoholics.     

Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis

The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.     

Interactions between penicillin-binding proteins (PBPs) and two novel classes of PBP inhibitors, arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones

Several non-beta-lactam compounds were active against various gram-positive and gram-negative bacterial strains. The MICs of arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones were lower than those of ampicillin and cefotaxime for methicillin-resistant Staphylococcus aureus MI339 and vancomycin-resistant Enterococcus faecium EF12. Several compounds were found to inhibit the cell wall synthesis of S. aureus and the last two steps of peptidoglycan biosynthesis catalyzed by ether-treated cells of Escherichia coli or cell wall membrane preparations of Bacillus megaterium. The effects of the arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-one derivatives on E. coli PBP 3 and PBP 5, Streptococcus pneumoniae PBP 2xS (PBP 2x from a penicillin-sensitive strain) and PBP 2xR (PBP 2x from a penicillin-resistant strain), low-affinity PBP 2a of S. aureus, and the Actinomadura sp. strain R39 and Streptomyces sp. strain R61 DD-peptidases were studied. Some of the compounds exhibited inhibitory activities in the 10 to 100 microM concentration range. The inhibition of PBP 2xS by several of them appeared to be noncompetitive. The dissociation constant for the best inhibitor (Ki = 10 microM) was not influenced by the presence of the substrate.     

Orchitis bei Serumkrankheit

Zusammenfassung Bericht über eine Orchiepididymitis im Rahmen einer Serumkrankheit bei einem zehnjährigen akzelerierten Jungen 13 Tage nach Injektion von 5 ml Diphtherieserum vom Pferd. Schlagartiger Rückgang auf Prednison. Vier weitere Fälle aus der Literatur. Hinsichtlich der bei unserem Patienten ebenso wie bei der Großzahl der Mumpsorchitiden u.a. gegebenen Altersdisposition lassen sich Zusammenhänge zwischen Organwahl und Organaktivität diskutieren, die auch durch zahlreiche andere analoge Beobachtungen aus Klinik und Experiment gestützt würden.

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Summary Report on an orchiepididymitis caused by serum sickness in a 10-year-old boy with acceleration of growth. Manifestation took place 13 days following an injection of 5 ml of horse-diphtheria-serum. Rapid amelioration after prednisone. Only four other cases seem to have been reported in the literature. In regard to the age disposition in our patients as well as in other cases of orchitis (caused by parotitis epidemica virus and others) connections between disposition and activity of organs should be discussed. Many other clinical and experimental observations underline this theory.

     

Diverticulitis with perforation into the peritoneal cavity.

Sigmoid diverticulitis with free perforation or perforation through the mesentery results in generalized peritonitis. Emergency surgical treatment is mandatory, but the most efficacious procedure has not been clearly established. Ten consecutive patients were treated by removal of the perforated sigmoid colon, temporary end colostomy and peritoneal toilet. All but one patient survived the initial procedure, and there were only four minor complications. The preoperative diagnosis was correct in 8 of the 10 patients. Analysis of the preoperative clinical findings revealed that a decision in favor of immediate operation was not difficult. The predominant clinical manifestations were severe abdominal pain and tenderness, fever, and elevation of the white blood cell count. The most reliable diagnostic finding was localization of the area of maximum tenderness to the left lower quadrant and suprapubic areas. While it is not applicable for all the pathologic manifestations of diverticulitis, sigmoid colectomy, temporary end colostomy and peritoneal toilet is efficacious therapy in perforative diverticulitis with free communication between the colonic lumen and the peritoneal cavity.     

Clinical vascular laboratory diagnosis of deep venous thrombosis.

The accuracy of our clinical vascualr laboratory was evaluated. Sixty-nine limbs (55 patients) were examined clinically for thrombophlebitis. All of these patients were then evaluated using segmental plethysmography and Doppler ultrasound techniques. Each limb was then studied with venography. In 57 of the 69 (82.6%) limbs evaluated, measurement of the maximum venous outflow accurately reflected the venographic findings. Doppler augmented venous sounds were correct when compared to venography in 77.6% of limbs. In the 59 limbs that exhibited clinical signs of deep venous thrombosis, only 35.6% had venographic confirmation of the diagnosis. The clinical vascular laboratory provides an accuracy of diagnosis of deep venous thrombosis not achieved by clinical examination. If both segmental plethysmography and Doppler ultrasound were negative, it was very unlikely that deep venous thrombosis had occurred.