Association of bone marrow fibrosis with inferior survival outcomes in chronic myelomonocytic leukemia

The impact of bone marrow fibrosis grade on the prognosis of patients with chronic myelomonocytic leukemia (CMML) remains controversial. Therefore, we examined the records of 82 patients diagnosed with CMML at our institution and summarized baseline characteristics and molecular profiles by subgroups of absent or mild (grades 0/1) and moderate (grade 2) fibrosis. Cox proportional hazards models were constructed to assess the prognostic significance of fibrosis grade. Grade 2 fibrosis was identified in 63 patients (76.8%), grade 1 in 16 patients (19.5%), and grade 0 in 3 patients (3.7%). Grade 2 fibrosis was associated with reduced hemoglobin levels (median 9.75 vs 11.0 g/dL in grade 0/1; p?=?0.04) and increased percentages of ringed sideroblasts (7.5 vs 0%; p?=?0.008). In multivariable analysis, grade 2 fibrosis was an independent predictor of poor overall survival (OS; 95% CI 1.32–6.35; HR 2.90; p?=?0.008), but not event-free survival (EFS; 95% CI 0.62–2.67; HR 1.28; p?=?0.50). Absolute neutrophil count (ANC) was found to impact OS (95% CI 1.01–1.09; HR 1.05; p?=?0.009), while both ANC (95% CI 1.00–1.07; HR 1.04; p?=?0.04) and peripheral blood blast percentage (95% CI 1.02–1.32; HR 1.16; p?=?0.02) impacted EFS. These results implicate fibrosis grade is an important indicator of prognosis, with high-grade fibrosis predicting inferior survival. Given the prevalence of marrow fibrosis in CMML, fibrosis grading should be incorporated into prognostic assessment and therapeutic decision-making.     

Alcohol Ingestion Impairs Host Defenses Predisposing Otherwise Healthy Mice to Pneumocystis carinii Infection

Pulmonary infection with Pneumocystis carinii, an opportunistic pathogen, is associated with a variety of immunosuppressive states, Including human immunodeficiency virus infection. We hypothesized that alcohol ingestion might compromise host defenses against this pathogen and, in an immunocompromised host, increase the severity of infection. This hypothesis was tested in both acute and chronic ethanol-treated normal and CD4⁺ T-cell-depleted mice challenged with P. carinii organisms. Normal and CD4⁺ T-cell-depleted mice were given an intraperitoneal injection of ethanol or saline 0.5 hr before P. carinii challenge and killed 3 hr later for bronchoalveolar lavage. Acute alcohol treatment decreased significantly tumor necrosis factor (TNF) activity and the number of polymorphonuclear leukocytes (PMNLs) recovered in the lavage in response to the pathogen. Depletion of CD4⁺ T-cells did not potentiate the effect of alcohol on the early inflammatory response to the pathogen any further. In normal animals, in vivo interferon (IFN)-γ pretreatment augmented significantly the P. carinii- stimulated lung TNF response and PMNL recruitment. However, IFN-γ pretreatment prevented the alcohol-induced suppression of TNF secretion without affecting the PMNL recruitment. The effect of chronic alcohol consumption on the severity of infection was studied in long-term, alcohol-fed normal and CD4⁺-depleted mice challenged with P. carinii organisms. Lung histopathology showed that P. carinii infection was present in >60% of the alcohol-fed mice and in none of the controls. Also, a significantly higher number of PMNLs were recovered in the lavage fluid of alcohol-fed mice with persistent infection. There was no difference in lavage fluid and cell culture supernatant TNF and reactive nitrogen intermediates release between the two groups. CD4⁺ T-cell depletion did not alter significantly the effect of alcohol on any of the aforementioned parameters. We conclude that chronic alcohol ingestion alone induces immunosuppression sufficient to permit pulmonary infection with P. carinii. One possible mechanism for the adverse effects of alcohol on host defenses against P. carinii may be through suppressed host release of cytokines including TNF-α and IFN-γ.     

Effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action

Essential hypertension is associated with impairment of both endothelial function and insulin action, and this has provided rationale for the use of antihypertensive agents that are at least neutral, if not beneficial, in these areas. This study examines the effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Sixteen patients with essential hypertension were recruited with 13 (3 men/10 women; median age, 55 years; range, 38 to 65 years) completing the study. A double-blind, placebo-controlled crossover study design was used. After a 6-week placebo run-in, there were two 12-week treatment periods of either placebo or doxazosin, separated by a 6-week wash out period. Subjects were studied at the end of each treatment period with endothelial function assessed by forearm plethysmography and insulin action by the hyperinsulinemic clamp technique. Blood pressure was significantly lowered by doxazosin (doxazosin 144 +/-3/86 +/- 2 mm Hg; placebo 159 +/- 3/96 +/- 1 mm Hg, P <.005 for both systolic and diastolic pressure; mean +/- SEM). Baseline forearm blood flow (FBF) was unchanged (doxazosin 4.9 +/- 0.9; placebo 4.0 +/- 0.7 mL x 100 mL(-1) x min(-1), P >.05), however, FBF responses (area under dose response curve, percentage change in infused:control arm ratio) to acetylcholine (endothelium-dependent vasodilation) were improved by doxazosin (doxazosin 58.6 +/- 11.7 standard units [SU]; placebo 22.1 +/- 7.0 SU, P =.03) with responses to sodium nitroprusside (endothelium-independent vasodilation) unchanged (doxazosin 40.3 +/- 5.5 SU; placebo 46.3 +/- 8.1 SU, P >.05). Exogenous glucose infusion rates to maintain euglycemia during hyperinsulinemia were not significantly different (doxazosin 30.4 +/- 0.9; placebo 32.3 +/- 1.0 micromol x kg(-1) min(-1), P >.05). Suppression of postabsorptive endogenous glucose production by insulin was also unchanged by treatment (doxazosin 65.6% +/- 7.5% suppression; placebo 68.3% +/- 11.2% suppression, P >.05). Doxazosin has a neutral effect on both peripheral and hepatic insulin action, but improves endothelium-dependent vasodilation. These results indicate that doxazosin can be used safely in patients with insulin resistance, while its positive effect on endothelial function may lessen the subsequent incidence of atherosclerosis.     

Laboratory and clinical experience in 55 patients with macroprolactinemia identified by a simple polyethylene glycol precipitation method

PRL exists in different forms in human serum. The predominant form is little PRL (molecular mass 23 kDa) with smaller amounts of big PRL (molecular mass 50--60 kDa) and at times big big or macroprolactin (molecular mass 150--170 kDa). The frequency and clinical consequences of macroprolactinemia have not been clearly established, mainly because of difficulty in identifying these patients biochemically. This previously required the use of gel filtration chromatography, which could not be used routinely. Recently, a screening test using polyethylene glycol (PEG) has been used to identify macroprolactin in serum. Consequently, this study was designed to examine the use of PEG precipitation in the identification of patients with a predominance of macroprolactin and to establish the clinical characteristics of such a cohort. Over 12 months, 18,258 requests for serum PRL were received and of these 1225 patients had a serum PRL more than 700 mU/L. A total of 322 of these patients (26%) had a percentage recovery after PEG precipitation of less than 40%, thus indicating the presence of a predominance of macroprolactin. Fifty-five of these patients were referred for detailed clinical assessment. Symptoms typical of hyperprolactinemia were not common in this cohort. None had sustained amenorrhea and eight have had oligomenorrhea at age less than 40 yr. One had galactorrhea. All had pituitary imaging, and four had a microadenoma with none having a macroadenoma. PEG precipitation allows easy identification of macroprolactin in routine clinical practice. As the clinical consequences of this entity at this stage seem relatively benign, referral and intensive investigation of these patients may not be necessary. However, follow-up of a large cohort is required to ensure that the long-term outlook is likewise benign. This would have important implications for both patients and healthcare systems.     

Serum bioavailability and tissue metabolism of testosterone and estradiol in rat salivary gland

The concentration of testosterone in saliva is probably in equilibrium with the concentration of cellular exchangeable testosterone in salivary gland, and these pools are a function of hormone transplant from the plasma compartment, and hormone metabolism in salivary gland cells. Both of these processes were examined in the present study using the carotid injection technique in normal and pilocarpine-stimulated ketamine-anesthetized rats. Both testosterone and estradiol were rapidly transported across salivary gland capillaries in vivo from the circulating albumin-bound pool. Estradiol, but not testosterone, was also rapidly transported into salivary gland from the circulating human sex hormone-binding globulin-bound pool. Hormone transport was several-fold greater than the capillary transport of [3H]bovine albumin, indicating that bound hormone was available for transport across salivary gland capillaries via an enhanced dissociation mechanism, with the plasma protein primarily residing in the plasma compartment. This result was confirmed by thaw-mount autoradiography, which showed diffuse distribution of [3H]testosterone in salivary gland, but vascular retention of [3H]bovine albumin. The concentration of exchangeable cellular testosterone in rat saliva was less than 4% of the total or plasma exchangeable testosterone in the rat. This marked discrepancy between the concentration of plasma and cellular exchangeable hormone suggested that there was rapid metabolism of androgen by salivary gland in vivo. This was confirmed by chromatographic separation of [3H] testosterone and labeled metabolites in homogenates of salivary gland. By 60 sec after injection, approximately 30% of the radioactivity in the salivary gland was in the form of androgen metabolites, which primarily comigrated with an androstenedione standard. The data indicate that albumin-bound testosterone, albumin-bound estradiol, and sex hormone-binding globulin-bound estradiol are all exchangeable in salivary gland capillaries. The low concentration of cellular exchangeable testosterone in salivary gland appears to be due to rapid tissue metabolism of this hormone. Thus, changes in androgen metabolism may alter salivary gland hormone concentrations independent of any change in the concentration of biologically active hormone in plasma.     

The incidence of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency among hirsute women

Late-onset congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a cause of hirsutism in adult women. Its reported frequency of occurrence in hirsute women has varied from 0-30%, but the number of patients studied was small. To establish the incidence of CAH, 83 unselected hirsute women were studied prospectively with a standard ACTH stimulation test. On the basis of an exaggerated response of serum 17 alpha-hydroxyprogesterone to ACTH, 1 patient with CAH was found, for an incidence of 1.2%. The 95% confidence limits for the incidence of CAH among hirsute women were 0% and 3.4%. Five of seven hirsute women without CAH whose serum 17 alpha-hydroxyprogesterone levels rose above 3 ng/ml in response to ACTH had simultaneous serum progesterone values consistent with recent ovulation. Since routine screening of all hirsute women by means of ACTH stimulation does not appear to be cost effective, reported cases of CAH were reviewed in order to discern potentially helpful clinical clues. Severe hirsutism, virilization, early onset of symptoms, short stature, familial occurrence, and regular menses were identified as the clinical characteristics associated with late-onset CAH.     

Retrospective attention enhances visual working memory in the young but not the old: An ERP study

Behavioral evidence from the young suggests spatial cues that orient attention toward task‐relevant items in visual working memory (VWM) enhance memory capacity. Whether older adults can also use retrospective cues (“retro‐cues”) to enhance VWM capacity is unknown. In the current event‐related potential (ERP) study, young and old adults performed a VWM task in which spatially informative retro‐cues were presented during maintenance. Young but not older adults' VWM capacity benefited from retro‐cueing. The contralateral delay activity (CDA) ERP index of VWM maintenance was attenuated after the retro‐cue, which effectively reduced the impact of memory load. CDA amplitudes were reduced prior to retro‐cue onset in the old only. Despite a preserved ability to delete items from VWM, older adults may be less able to use retrospective attention to enhance memory capacity when expectancy of impending spatial cues disrupts effective VWM maintenance.