Congenital Nonspherocytic Hemolytic Anemia, Associated with Glutathione Deficiency of the Erythrocytes: Hematologic, Biochemical and Genetic Studies

1. A new biochemical defect of erythrocytes is described: glutathionedeficiency (reduced glutathione less than 10 per cent of the amount of reducedglutathione in normal erythrocytes).

2. The defect is associated with a clinical picture of congenital nonspherocytic hemolytic anemia which is fairly well compensated.

3. The results of a family study are consistent with an autosomal recessivepattern of inheritance.

4. Labeling with Na₂Cr⁵¹O₄ has a damaging effect on glutathione-deficienterythrocytes. The erythrocyte life span, as estimated by a serological method(Ashby), was markedly shortened (30 days instead of 100-120 days).

5. Red cell destruction could be increased by the administration of primaquine.

6. Secondary to the glutathione deficiency, low glyoxalase activity wasobserved. The glutathione-reducing capacity, glycolytic activity, and the ATPlevel of the abnormal red cells were found to be within the normal range.

7. On incubation of the glutathione-deficient erythrocytes in vitro withglycine-C¹⁴ and glutamine-C¹⁴, no formation of labeled glutathione could bedemonstrated.

Submitted on October 7, 1964 Accepted on June 29, 1965     

ALTERATIONS IN GAP JUNCTION PROTEIN EXPRESSION IN HUMAN BENIGN PROSTATIC HYPERPLASIA AND PROSTATE CANCER

PURPOSE: Gap junctions composed of connexin proteins have an essential role in intercellular communication and differentiation. Dysregulation of connexin expression is believed to have a role in carcinogenesis. The human prostate has been reported to express connexin 32 and 43. However, the expression pattern in prostate cancer is controversial, while to our knowledge connexin expression has not been reported in benign prostatic hyperplasia (BPH). To understand the potential involvement in prostate disease connexin 32 and 43 expression was evaluated in a series of normal prostate, BPH and prostate cancer specimens that were surgically removed due to bladder outlet obstruction. MATERIALS AND METHODS: Frozen sections of 23 normal, 43 BPH and 40 cancer involved prostates were evaluated for the presence, staining intensity and pattern of connexin 32 and 43 by immunocytochemical testing. RESULTS: In all specimens examined connexin 43 stain was punctate along the borders of the basal epithelial cells, whereas connexin 32 immunolocalized to luminal epithelial cells. In normal prostate connexin 43 and 32 were present in 87% and 65% of specimens, respectively, at low to moderate stain intensity. Importantly none of the normal samples were negative foreach connexin. In BPH specimens there was a marked increase in the incidence and intensity of connexin 43 and 32 immunostaining within epithelial cells. In addition, 23% of BPH samples showed strong connexin 43 expression in stromal cells. In contrast, connexin was decreased in prostate cancer specimens, of which 65% and 38% were negative for connexin 43 and 32, respectively, and 28% were negative for each type. In poorly differentiated tumors connexin 43 and 32 were present in only 10% and 40% of tumors, respectively, at low immunostaining intensity. CONCLUSIONS: In normal human prostate basal cells communicate via connexin 43 gap junctions, whereas luminal cells communicate via connexin 32 gap junctions. In BPH gap junctional intercellular communication is increased in epithelial and stromal cells, which may have a role in BPH pathogenesis. In prostate cancer gap junctional intercellular communication is decreased, is as indicated by decreased expression of connexin 43 and 32 with severe loss in poorly differentiated prostate cancer. These alterations in connexin expression may have a role in dedifferentiation and tumor progression.     

Cost‐effectiveness of ruling out deep venous thrombosis in primary care versus care as usual

Summary. Background: Referral for ultrasound testing in all patients suspected of DVT is inefficient, because 80–90% have no DVT. Objective: To assess the incremental cost‐effectiveness of a diagnostic strategy to select patients at first presentation in primary care based on a point of care D‐dimer test combined with a clinical decision rule (AMUSE strategy), compared with hospital‐based strategies. Patients/Methods: A Markov‐type cost‐effectiveness model with a societal perspective and a 5‐year time horizon was used to compare the AMUSE strategy with hospital‐based strategies. Data were derived from the AMUSE study (2005–2007), the literature, and a direct survey of costs (2005–2007). Results of base‐case analysis: Adherence to the AMUSE strategy on average results in savings of €138 ($185) per patient at the expense of a very small health loss (0.002 QALYs) compared with the best hospital strategy. The iCER is €55 753($74 848). The cost‐effectiveness acceptability curves show that the AMUSE strategy has the highest probability of being cost‐effective. Results of sensitivity analysis: Results are sensitive to decreases in sensitivity of the diagnostic strategy, but are not sensitive to increase in age (range 30–80), the costs for health states, and events. Conclusion: A diagnostic management strategy based on a clinical decision rule and a point of care D‐dimer assay to exclude DVT in primary care is not only safe, but also cost‐effective as compared with hospital‐based strategies.     

Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial

In the treatment of serious infection by aminoglycoside antibiotics multiple daily treatment with netilmicin is considered to be the least toxic. Studies comparing netilmicin with gentamicin using the less toxic once-daily schedule are lacking. A randomized prospective study was designed to evaluate the efficacy and toxicity of once-daily netilmicin with gentamicin treatment in patients with serious infections. Consecutive patients with serious infections were randomized between gentamicin 4 mg/kg q24h iv or netilmicin 5.5 mg/kg q24h iv. Exclusion criteria were neutropenia or severe renal failure. A good clinical response was observed in 50 of the 54 evaluable patients (92.6%) treated with gentamicin and in 48/52 (92.3%) netilmicin treated patients. Nephrotoxicity developed in 5/72 (6.9%) gentamicin patients and in 10/69 (14.5%) treated with netilmicin. Audiometry was performed with high-frequency audiometry when possible; no significant differences were found between the two aminoglycosides. We conclude that with once-daily treatment no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated.     

Prevalence of Hearing Impairment and Hearing Complaints in Older Adults: A Study in General Practice

In one general practice, 660 people aged 60 years or over werescreened by means of pure tone audiometry and a specific questionnaireto assess the prevalence of hearing impairment and hearing complaints.Hearing impairment was defined as an average loss of 35 dB ormore in the 1, 2 and 4 kHz frequencies in one or both ears.In total, 37.4% (95% Cl, 33.3–41.1%) of the participantswas hearing impaired. The prevalence was higher in men (55.1%)than in women (44.9%) and clearly increased with age in bothsexes. The prevalence of hearing complaints in terms of hearingdifficulties and/or tinnitus, was 37.3% (95% Cl, 33.6–41.0%),and increased with age, especially in women. Of the subjectswith hearing impairment, 64.4% reported hearing complaints.Of the subjects without hearing impairment, 21.1% experiencedhearing complaints. This study suggests that screening olderadults with relatively simple methods, may identify a largeproportion of men and women in general practice with hearingproblems. Providing information to both patients and generalpractitioners about the possibilities of hearing improvementis a crucial step in making people become more aware of hearingproblems. This could ultimately lead to improvement of the qualityof life of older men and women with hearing problems.     

Prevention of venous thromboembolism with an oral factor Xa inhibitor,YM150, after total hip arthroplasty. A dose finding study (ONYX‐2)

Background: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. Objectives: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. Patients/methods: Patients were randomized to postoperative, once‐daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double‐blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. Results: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose‐related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. Conclusions: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.