Identification of the hydration state in emergency patients: correlation between caval index and BUN/creatinine ratio.

BACKGROUND: Dehydration is a frequent clinical problem. No single laboratory value has been found to be accurate; however, the BUN/Creatinine Ratio appears the most sensitive parameter. The respiratory variation (Caval Index, CIn) in the diameter of the inferior vena cava has been investigated as a non-invasive marker for the intravascular volume status. AIM: The present study is performed with the aim to explore the relationship between CIn and BUN/creatinine ratio. PATIENTS AND METHODS: This prospective, observational study was conducted at Emergency Department (ED) of San Paolo Hospital (Savona, Italy), in October 2011. RESULTS: 113 patients were considered eligible (mean age of 63 years). We found a good correlation between CIn and BUN/Cr Ratio (Pearson Index 0.76, p < 0.001). Receiver operator characteristic curve (ROC) analyses indicated that the maximum value was 0.884 (p < 0.0001) and corresponded to CIn 60.7%, (sensitivity 79%, specificity 89%). CIn was a good predictor for patients with BUN/Cr ratio greater than 20, and was particularly strong in determining patients with lower BUN/Cr ratio. DISCUSSION: Our study suggests that inferior vena cava could provide indications on the state of hydration of the patients: we found that a caval index greater than or equal to 60% was associated with a BUN/Cr Ratio over 20, which is considered an important marker for dehydration. Therefore, bedside sonography can give emergency physicians immediate information on patient volume status long before obtaining laboratory findings. CONCLUSIONS: Our study seems to support the hypothesis that CIn can be a useful bedside marker to predict dehydration in Emergency Department (ED) patients.

Azidothymidine-induced depression of murine hemopoietic progenitor cells.

The toxicity of the antiviral drug 3'-azido-3'-deoxythymidine was studied in vivo on murine hemopoietic progenitor cells and peripheral blood cells. The drug induced a marked decrease of all tested populations, showing a severe toxicity on hemopoiesis.

Azidothymidine and interferon-alpha in vitro effects on hematopoiesis: protective in vitro activity of IL-1 and GM-CSF.

Preclinical and clinical studies with an azidothymidine (AZT)/interferon-alpha (IFN-alpha) combination resulted in a marked and synergistic antiretroviral activity. The administration of the two drugs in HIV-seropositive patients affected with Kaposi's sarcoma, however, induced neutropenia, thrombocytopenia, and, in some cases, anemia. A possible means to improve the therapeutic index of AZT and/or IFN-alpha in AIDS patients could be the addition of hematopoietic growth factors. In vitro activity of cytokines on the hematotoxicity of the AZT-IFN-alpha association has not yet been studied. We have performed an in vitro study to evaluate the toxicity of AZT, IFN-alpha, or both on peripheral blood hematopoietic progenitors (CFU-GM and BFU-E) and to assess the activity of interleukin 1 (IL-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), or both in modifying AZT-IFN-alpha hematotoxicity. Results indicate that AZT, IFN-alpha, and combinations of the two have a dose-dependent inhibitory effect on the in vitro growth of peripheral blood hematopoietic progenitors. Combinations of AZT and IFN-alpha inhibited CFU-GM and BFU-E proliferation in an additive manner. Neither IL-1 nor GM-CSF alone was able to induce a significant reduction of AZT-induced damage. Only the addition to the cultures of both cytokines partially curbed the antiproliferative activity of AZT at low dosages.

Hemotoxic effects on mice of combined administration of azidothymidine and acyclovir.

This study reports the effects of a combination of azidothymidine (AZT) plus acyclovir (ACV) on both pluripotent (spleen colony-forming units, CFU-S) and committed (granulocyte-macrophage colony-forming units, CFU-GM; erythroid burst-forming units, BFU-E) murine hemopoietic progenitors. Administration of AZT alone was associated with severe hemotoxicity, as shown by the marked decrease of all the hemopoietic progenitor populations tested, that is, CFU-S, CFU-GM, and BFU-E. This, however, was followed by a prompt recovery of hemopoiesis. Administration of ACV alone did not modify the hematological parameters studied, whereas the combined administration of AZT and ACV led to changes in peripheral blood cells and bone marrow hemopoietic progenitors that were, on the whole, not significantly different from those observed with AZT alone. Only the decrease in CFU-S was significantly more severe, but their recovery was as rapid as that of the committed progenitors. Thus, in this experimental setting, the addition of ACV to AZT does not appear to increase the hemotoxicity of the latter.

Serum erythropoietin increase in patients receiving adjuvant therapy with 5-fluorouracil and leucovorin.

High-dose anticancer drugs have been shown to induce an increase in serum erythropoietin (sEpo) levels not mediated by hypoxia. In this study, sEpo was assessed in seven patients who had been administered a course of 5-day leucovorin-modulated 5-fluorouracil (5-FU-LV) as an adjuvant therapy after the removal of colon cancer. During this study, the mean hemoglobin (Hb) concentration stayed at a constant level, peripheral blood (PB) reticulocytes showed an early, sharp decline, and sEpo levels progressively increased for 15 days after the start of chemotherapy. These results appear to indicate that the increase in sEpo, which was not related to anemia, may have followed from the administration of a cytotoxic drug at doses used in routine, clinical practice.

In vitro synergistic inhibition of human bone marrow hemopoietic progenitor growth by a 3'-azido-3'-deoxy-thymidine, 2',3'-dideoxycytidine combination.

In vitro growth of human normal bone marrow granulocyte-macrophage colony forming units (CFU-GMs) and erythroid burst forming units (BFU-Es) was dose-dependently inhibited by 3'-azido-3'deoxythymidine (AZT) (from 0.1 microM to 4 microM) and 2',3'-dideoxycytidine (ddC) (from 0.01 microM to 1.0 microM). These ranges included minimum in vitro inhibitory concentrations to HIV-1 and concentrations corresponding to plasma level achievable in vivo. A synergistic inhibitory effect, statistically highly significant, was observed when combinations of the two drugs were added to cultures. This severe in vitro toxicity of ddC and the synergistic toxicity of AZT-ddC combinations on hemopoietic progenitor cells should be considered when the two drugs are administered in concurrent or alternating regimens.

Interferon-alpha inhibits CFU-GM mobilization following chemotherapy and G-CSF administration.

Changes in routine hematologic data and in circulating granulocyte-macrophage colony-forming units (CFU-GM) during granulocyte colony-stimulating factor (G-CSF) administration were evaluated in non-small cell lung carcinoma (NSCLC) patients treated with a combination of 5-fluorouracil (5-FU) and cisplatin (DDP) with and without the addition of interferon-alpha (IFN-alpha). The patterns of leukocyte changes following chemotherapy plus G-CSF were similar in both the IFN-alpha-inclusive and the IFN-alpha-devoid courses. However, the twofold increase in CFU-GM observed in patients receiving chemotherapy plus G-CSF was completely absent following the course including IFN-alpha. The activity of G-CSF on the hematologic pattern is seemingly affected by its combination with IFN-alpha treatment. Mechanisms of the possible in vivo interaction among IFNs and hematopoietic growth factors remain to be elucidated.

Regional pharmacokinetic selectivity of intrapleural cisplatin.

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Protective effect on cisplatin hematotoxicity by procaine hydrochloride.

The ability of procaine hydrochloride (P.HCl) to modulate the effects of cisplatin (DDP) on pluripotent (CFU-S) and committed (CFU-GM) murine hemopoietic stem cells was investigated. DBA/2NCrlBRF1 mice received DDP alone (10 and 16 mg/kg body wt. single i.p. injection) or in combination with P.HCl (40 mg/kg body wt. single i.p. injection). Hemopoietic progenitor cell (HPC) time survival curves were determined up to 14 days following treatment. The simultaneous administration of the lower DDP dose together with P.HCl greatly reduced the hemotoxicity of the antitumoral drug, while this protection was not significant with the higher DDP dose. These results support a role for P.HCl in protecting against DDP hematological toxicity.

In vitro activity on myeloid progenitors of a combination of 2-chloro-2'-deoxyadenosine and interferon alpha: the effects of IL-1 and GM-CSF.

The toxic effects of a combination of 2-chloro-2'-deoxyadenosine (CDA) and interferon alpha (IFN-alpha), with and without addition of interleukin 1 (IL-1) and/or granulocyte macrophage colony stimulating factor (GM-CSF), on the in vitro growth of peripheral blood granulocyte macrophage committed progenitors (CFU-GM) from 10 normal subjects were investigated. CDA concentration ranged from 15.6 nmol/l to 1 mumol/l, IFN-alpha sole concentration was 10 IU/ml. IL-1 and/or GM-CSF were added at concentrations of 2000 pg/ml and 10 ng/ml, respectively. CDA induced a dose dependent inhibitory effect on CFU-GM growth. Addition of IFN-alpha increased CFU-GM inhibition induced by CDA only at lower concentrations of the latter. IL-1 and GM-CSF, separately or in combination, did not counteract the inhibitory activity of the CDA-IFN-alpha combination.

Pre-emptive analgesia in rats with artificial ureteric calculosis. Effects on visceral pain behavior in the post-operative period.

'Pre-emptive' analgesia is a controversial issue in both the clinical and experimental literature on pain. This paper investigates the effect of chronic (4 days) administration of morphine or ketoprofen initiated pre- or post-operatively on behavioral indicators of visceral pain and referred hyperalgesia in an animal model of artificial ureteric calculosis. In the morphine experiment, female Sprague-Dawley rats were treated i.p. with saline or morphine sulphate (2.5 or 5 mg/kg/day) starting either 45 min before or 45 min after surgery (pentobarbital anesthesia) for stone implantation in the left ureter, until the 4th day after intervention. Behavioral crises of ureteric pain were recorded (video-tape) in all rats over 4 days post-operatively. Number, duration and complexity of crises of stone-rats were significantly and dose-dependently reduced by administration of morphine with respect to saline in an identical manner for the pre- and post-operative treatment. In the ketoprofen experiment, rats were given saline or ketoprofen (15 mg/kg/day, in 3 i.p. injections per day) starting either pre- or post-operatively with the same paradigm as for the morphine study. Vocalization thresholds to electrical stimulation of the left oblique musculature were measured daily for 3 days pre- and 4 days post-operatively. Muscle hyperalgesia (post-operative decrease in threshold with respect to pre-stone implantation) was significantly reduced in extent and duration in ketoprofen with respect to saline-injected animals but no difference was found between the pre- and post-operative treatment. It is concluded that pre-emptive administration of morphine or ketoprofen has no advantage in reducing behavioral indicators of visceral pain and referred hyperalgesia in this animal model.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Expression and genomic configuration of GM-CSF, IL-3, M-CSF receptor (C-FMS), early growth response gene-1 (EGR-1) and M-CSF genes in primary myelodysplastic syndromes.

Peripheral blood mononuclear cells from seventeen patients with primary myelodysplastic syndromes (MDS) in advanced stage were enriched for blasts and tested for (1) karyotype, (2) genomic configuration and (3) expression of IL-3, GM-CSF, FMS and EGR-1 genes which are all located on the long arm of chromosome 5. The expression of the M-CSF gene, that has been recently reassigned to the short arm of chromosome 1 (lp), was also investigated. Aims of the study were to (1) assess the potential role of the expression of these genes in the maintenance and expansion of the neoplastic clones and (2) search for constitutional losses or rearrangements of one allele followed by a deletion of the second allele of the same genes in the leukemic cells. The latter issue was investigated by comparing, in 8 cases, constitutive DNA from skin fibroblasts with leukemic DNA. Eleven of the 17 patients had abnormal karyotypes. The M-CSF gene was expressed in 6 cases and the FMS and the EGR-1 genes were expressed in 2 of the latter cases. An autocrine mechanism of growth could be hypothesized only for the 2 patients whose cells expressed both the M-CSF and FMS genes. No germline changes or rearrangements were observed in any of the genes studied. Thus, deregulation of genes encoding for certain hemopoietic growth factors or receptors does not seem to represent a major mechanism of MDS progression.

Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women.

This study investigated the impact of algogenic conditions of the reproductive organs upon urinary pain perception in women. A 5-year survey was conducted among 69 fertile women with calculosis of one upper urinary tract via an ad-hoc questionnaire. At both retrospective (3 years) and prospective (2 years) investigation, dysmenorrheic women (D) reported more colics than non-dysmenorrheic women (ND) (P<0.001) and women with previous dysmenorrhea treated with estroprogestins (DH)(P<0.05). Pain thresholds (electrical stimulation) of the oblique musculature ipsilateral to the stone (L1, site of referred hyperalgesia from upper urinary tract) were lower in D than in ND (P<0.01) and DH (P<0.05). Calculosis women with asymptomatic endometriosis / ovarian cysts also reported more colics (6-month prospective study) and greater threshold lowering (P<0.05) than women with calculosis alone. The results show enhancement of urinary pain / hyperalgesia by both manifest and latent algogenic conditions of the female reproductive organs. This enhancement could derive from neuronal sensitization in spinal segments of common projection of the two visceral districts (T10-L1).

Hyperfibrotic myelodysplasia - a possible new entity (review).

Fibrosis of the bone marrow may be present in various hematologic diseases such as myeloproliferative diseases (MPD) and acute myeloid leukemias (AML). In primary myelodysplastic syndromes (MDS) myelofibrosis is a relatively rare event. Patients affected by MDS with myelofibrosis (H-MDS) present intriguing features that give rise to the hypothesis that H-MDS might represent a new entity. The purpose of this concise review is to summarize the contrasting opinions of the authors who have described some series of H-MDS patients. Many characteristics induce one to distinguish H-MDS from classical MDS, so that the former has been considered each time as a transitional stage between MDS and MPD, an acute transformation of an MPD, or an AML from the beginning. The pathogenetic mechanism of the fibrosis of the bone marrow may be similar to sic sic of the MPD in which a stimulus to secrete reticuline or collagen derives from abnormal marrow megakaryocytes. Importance of karyotype abnormalities are discussed. Clinical features of the syndrome are rather heterogeneous; evaluation of the survival of the described single cases reveals that mean survival is not significantly different from classical MDS. Finally, trephine biopsy and the cytogenetic study are necessary to permit the diagnosis of H-MDS. However, because of the relatively low number of cases, series of patients are necessary to correctly classify this syndrome.

Failure of N-acetylcysteine to protect against cis-dichlorodiammineplatinum(II)-induced hematopoietic toxicity in mice.

In view of the results showing a decrease in cis-dichlorodiammineplatinum(II) (cis-DDP) nephrotoxicity after administration of thiol donors, this study was carried out to test the possibility that N-acetylcysteine (NAC) was active against myelodepressive effects of the anticancer drug. Cis-DDP (15.5 mg/kg body weight, i.v.) was administered to control mice and to mice treated simultaneously or 1 h later with NAC (800 mg/kg body weight, i.v.). At various times after treatment, up to 11 days, assessments were made of peripheral blood cell levels and bone marrow progenitor cell (CFUs and CFUc) concentrations. Cis-DDP caused a decrease in hemopoietic precursor cells in the order of that caused by other hemopoietic precursor cells in the order of that caused by other myelodepressive drugs, whereas there was only a slight decrease in peripheral blood WBC. In this experimental setting, NAC administration did not afford significant protection against platinum toxicity on bone marrow precursors or peripheral blood cells.

Diltiazem does not increase the in vivo sensitivity of murine hemopoietic progenitor cells to doxorubicin.

The effect of doxorubicin and the calcium antagonist, diltiazem, on murine hemopoietic progenitor cells was studied in vivo. Dose-survival curves of murine bone marrow colony forming units (CFU)--spleen and granulocyte macrophage--were determined by in vivo and in vitro methods in DBA/2NCr/BR mice treated with doxorubicin alone or by simultaneous administration of doxorubicin (DX) and diltiazem (DTZ). Time response of bone marrow hematopoietic progenitor cells (HPC) was followed in mice similarly treated. Combination of DTZ with DX did not change the toxic effect of the latter on hemopoietic cells, either in the dose-survival model or in the time-related experiment.

Hematotoxicity of 5-fluorouracil and alpha-interferon on the human normal hemopoietic progenitors.

The toxic effects of a combination of 5 fluorouracil (5-FU) and interferon alpha on normal human hemopoietic progenitors were assessed in vitro. CFU-GM growth was evaluated following 1 h incubation of bone marrow cell suspension with 5-FU 100 micrograms/ml or IFN-alpha 2a 1000 U/ml, or with both drugs, either simultaneously or sequentially added. IFN-alpha did not show toxic effects on normal human hemopoietic progenitors and the severe toxicity of 5-FU on the latter was not modified by IFN-alpha. These results suggest that the changes observed in vivo of 5-FU toxicity induced by IFN-alpha should be attributed to indirect effects of the latter.

Hematotoxicity of 5-fluorouracil-leucovorin in a setting of adjuvant chemotherapy.

Changes of granulocyte macrophage colony forming units (CFU-GM) were assessed in peripheral blood of patients treated with 5-Fluorouracil-Leucovorin adjuvant chemotherapy after removal of colon cancer. The clinical and hematological state of the patients was steady and as far normal as possible. Leucocyte counts did not show significant changes. The mean peripheral blood level of CFU-GM significantly decreased following 5FU-LV infusion, reaching nadir by day 15. These changes of hemopoietic progenitors, not detected by routine hematic cell counts, point to a perturbation of the granulopoietic system by the 5FU-LV association also at doses used in adjuvant chemotherapy.

Leucovorin antagonizes the effects of trimetrexate on mouse hemopoietic progenitors.

Trimetrexate (2, 4, diamino -5- methyl - 6 [3, 4, 5, trimethoxyanilino) methyl] quinazoline) (TMQ) is a non-classic folate antagonist that is used as an antineoplastic and antipneumocystis agent with promising results. TMQ and methotrexate (MTX) toxicities are comparable. Leucovorin (N-5-formyltetrahydrofolate) (LV) is used to prevent the toxic effects of MTX. In this study the effects of LV on TMQ induced hemopoietic progenitor damage are studied in a murine model. Changes of pluripotent stem cells (colony forming units spleen, CFU-S), granulocyte-macrophage committed progenitors (GM-CFC), erythroid committed progenitor (BFU-E) levels in the bone marrow were followed after administration to mice of a single dose of TMQ or of simultaneous injection of TMQ and LV. Results show that the latter significantly reduces the effects of the former on peripheral blood cells and on hemopoietic progenitors.