Effect of 2'-deoxycoformycin on erythroid, granulocytic, and T- lymphocyte colony growth

The finding of elevated intracellular levels of adenosine deaminase (ADA) in some patients with acute lymphoblastic leukemia has led to attempts to control this disease with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF). Because of clinical reports indicating its relative freedom from myelotoxicity, we have tested the effects of this drug on erythroid, granulocytic, and T-lymphocyte colony formation by normal marrow and peripheral blood cells. While clinically the drug has been found to be active at serum concentrations of approximately 10 microM, we have tested it at concentrations up to and including 1 mM. It was found that both erythroid and granulocytic colony growth was completely unaffected by 1 mM dCF, a concentration at least 2 magnitudes higher than that necessary to totally ablate intracellular ADA levels. T-lymphocyte colony growth was unaffected by 100 microM dCF, but at 1 mM some inhibition was observed. These findings therefore indicate that dCF, while able to cause leukemic cell lysis in vivo, has no inhibitory effect on the proliferative capacity of normal hematopoietic cells.     

Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen

Platelet thrombospondin interacts with plasminogen in a specific and saturable manner. Thrombospondin was found to specifically bind to plasminogen and the nonenzyme chain of plasmin. Preincubation of 125I- labeled thrombospondin with 30 mmol/L lysine was without effect in the binding of thrombospondin to immobilized plasminogen; preincubation of 125I-labeled plasminogen with 30 mmol/L lysine, on the other hand, significantly reduced the binding of plasminogen to immobilized thrombospondin, suggesting that the interaction of thrombospondin with plasminogen is not the direct result of the lysine binding sites of plasminogen. Arginine and benzamidine, ligands known to specifically bind to the kringle 5 domain of plasminogen, blocked the binding of thrombospondin to plasminogen. Limited elastase proteolysis of plasminogen and plasmin resulted in the generation of two distinct thrombospondin binding domains, one of which was retained on lysine- agarose. The isolation and amino-terminal analysis of these domains following elastase proteolysis of plasminogen identified them, respectively, as a domain containing kringle structures 4 and 5 and plasmin and the other domain consisting of kringle 5-plasmin. A 16- residue synthetic peptide, which represents the amino acids linking kringle 4 to kringle 5 (residues 435-450 of native plasminogen), was without effect in either binding to thrombospondin or blocking the binding of thrombospondin to plasminogen. Plasminogen, therefore, possesses a single thrombospondin interactive site that is independent of, but influenced by, the lysine binding site containing kringle structures and most likely is located within the kringle 5 domain.     

How Does Aging Affect Presentation and Management of Biliary Stones?

Common bile duct (CBD) stones are common in elderly adults, but the effect of aging on the presentation of CBD stones remains to be evaluated. Recent studies have demonstrated that the clinical presentation of CBD stones may vary with age. Younger adults may present with classical biliary colic symptoms, whereas elderly adults may have no unapparent clinical features. Younger adults with CBD stones were significantly more likely to have abnormal liver function tests than those without. The sensitivity and accuracy of transabdominal ultrasound scans in screening for CBD stones increases with age. Antibiotic agents should be promptly administered to individuals with CBD stones complicated by cholangitis, but the effects of pharmacotherapy on renal function should be considered in elderly adults. Endoscopic retrograde cholangiopancreatography (ERCP) is considered to be first‐line treatment for CBD stones, and endoscopic biliary sphincterotomy (EST) or endoscopic papillary balloon dilation (EPBD) along with ERCP is an adequate biliary drainage method in individuals with CBD stones. EPBD has a lower bleeding risk but higher post‐ERCP risk of pancreatitis than EST. Longer‐duration (>1 minute) EPBD may be preferred over EST because it is associated with a comparable risk of pancreatitis but a lower rate of overall complications, although recurrent cholangitis or unfavorable outcomes will increase during CBD dilation or in the presence of residual CBD stones.     

The First Reported Case of Anti-Dob Causing an Acute Hemolytic Transfusion Reaction

The antibodies of the Dombrock blood group system have only rarely been encountered in transfusion practice, and anti-Do^b has not previously been implicated in an acute hemolytic transfusion reaction. We have encountered the first such case involving a chronically transfused black female with hemoglobin SS disease and multiple antibodies in her serum. During a previous admission for sickle cell crisis, the patient received 3 units of compatible blood with no untoward effects. Serum obtained 21 days later contained, in addition to the known antibodies, anti-S plus an unidentified antibody showing characteristics of HTLA. Blood lacking the E, K1, Fy(a), Jk(b) and S antigens was obtained, and 2 least incompatible units were transfused. While administering the second unit, the patient complained of fever and low back pain, and hemoglobinemia was detected. Anti-Do^b was identified in the post-reaction samples by absorption-elution tests, and the patient was confirmed to be Do(a+b–). The first unit transfused during this hemolytic episode tested Do (b+). This case, and a similar case involving anti-Do^a reported in 1986, strengthens the belief that Dombrock antibodies are clinically significant and illustrates the need for their differentiation, prior to transfusion from less clinically significant HTLA antibodies.     

Risk factors for the delayed viral clearance in COVID‐19 patients

Comorbidities are important for the disease outcome of COVID‐19, however, which underlying diseases that contribute the most to aggravate the conditions of COVID‐19 patients are still unclear. Viral clearance is the most important laboratory test for defining the recovery of COVID‐19 infections. To better understand which underlying diseases that are risk factors for delaying the viral clearance, we retrospectively analyzed 161 COVID‐19 clinical cases in the Zhongnan Hospital of Wuhan University, Wuhan, China between January 5 and March 13, 2020. The demographic, clinical and laboratory data, as well as patient treatment records were collected. Univariable and multivariable analysis were performed to explore the association between delayed viral clearance and other factors by using logistic regression. Survival analyses by Kaplan‐Meier and Cox regression modeling were employed to identify factors negatively influencing the viral clearance negatively. We found that hypertension and intravenous immunoglobulin adversely affected the time of viral RNA shedding. Hypertension was the most important risk factor to delay the SARS‐CoV‐2 virus clearance, however, the use of Angiotensin‐Converting Enzyme Inhibitors(ACEI)/Angiotensin Receptor Blockers(ARB) did not shorten the time for virus clearance in these hypertensive patients’ virus clearance. We conclude that patients having hypertension and intravenous immunoglobulin may delay the viral clearance in COVID‐19 patients.     

Society stress and peptic ulcer perforation

To examine the relationship between society stress and peptic ulcer perforation, time-trend analysis was performed on the annual incidence of perforated peptic ulcer per 100 000 population in Hong Kong during the years 1962–85, when Hong Kong, as a developing city, went through significant socio-economic and political changes, and the trend was correlated with specially designed and validated society stress scores estimated annually during the same period. The society stress scores were derived independently by two expert panels blinded to the purpose of the study, one selecting and categorizing negative news events for Hong Kong during this period, and the other weighing the categories and scoring the impact of the news on Hong Kong. The incidence of perforation increased significantly during the years and manifested three distinct peaks, which coincided with the worst economic recession in Hong Kong, the influx of mainlander Chinese and Vietnamese boat people, and the Sino-British negotiation on the sovereignty of Hong Kong after 1997. Both linear and autoregression analysis, the latter taking into consideration point fluctuations in rates, showed that perforation rates correlated significantly with the society stress scores (r= 0.57, P < 0.002). The peak effects and the significant correlations indicate that an association exists between society stress and peptic ulcer perforation, and suggest that chronic society stress plays an important role in the aetiology of this condition, although the relatively low r value also suggests the presence of other aetiological factors.     

Alogliptin Use in Elderly People: A Pooled Analysis from Phase 2 and 3 Studies

OBJECTIVES: To compare the efficacy and safety of alogliptin, a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, in elderly (≥65) and younger (<65) patients with type 2 diabetes mellitus.
DESIGN: Pooled analysis of six randomized, double-blind, placebo-controlled studies of alogliptin.
PARTICIPANTS: Patients aged 18 to 80 with type 2 diabetes mellitus and inadequate glycemic control.
INTERVENTIONS: Elderly (mean age 70.0; n=455) and younger (mean age 51.8; n=1,911) patients received alogliptin 12.5 mg (n=922), alogliptin 25 mg (n=910), or placebo (n=534) for 26 weeks (12 weeks in a Phase 2 study). The studies evaluated alogliptin as monotherapy and coadministered with pioglitazone, glyburide, metformin, or insulin.
MEASUREMENTS: Efficacy endpoints included change from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, and lipid values. Safety variables included hypoglycemic events, adverse events, and blood pressure.
RESULTS: Least-squares mean HbA1c decreased from baseline by 0.7% and 0.8% in elderly patients receiving alogliptin 12.5 and 25 mg, respectively, and 0.5% and 0.6%, respectively, in younger patients ( P <.001 for both alogliptin doses vs placebo for both age groups P =.70 for 12.5 mg and .68 for 25 mg for differences between age groups). Results were similar for FPG. Incidence of hypoglycemia was 8.3% or less in all alogliptin groups (≤10.5% for placebo), with no apparent difference between elderly and younger patients. Changes in weight were negligible in all treatment groups in both age categories. The safety profiles of alogliptin were similar in the age and dose groups.
CONCLUSION: Alogliptin was effective and well tolerated in the elderly patients enrolled in these studies. Improvements in HbA1c were similar to those seen in younger patients, and no increase in the risk of hypoglycemia, weight gain, or other adverse events was apparent in elderly patients.