Increase of Plasma Transforming Growth Factor Beta (TGFβ) During Immunotherapy with IL-2

Interleukin-2 (IL-2) is a lymphokine with pleiotropic activities on the immune system. When administered in vivo, besides inducing unrestricted tumor cytotoxicity, it is also responsible for the secondary release of other lymphokines, such as IL-1, TNF, and marrow growth factors, which may mediate some of the clinical toxicities (as well as therapeutic effects) seen during IL-2 immunotherapy. Among the clinical effects of IL-2, we previously reported thrombocytopenia and IL-2-induced in vitro inhibition of platelet aggregatiori accompanied by rapid secretion of alpha-granule components such as platelet factor 4 (PF4) and beta-thromboglobulin. Platelets coiistitute one of the largest storage forms of TGFβ. Preliminary evaluation of this factor in patients receiving IL-2 had indicated that plasma TGFβ activity increased in cancer patients following IL-2 therapy. We report a more detailed study of the quantitation of TCFβ activity, in the plasma of 23 cancer patients treated with IL-2 immunotherapy. Of interest, we found that although elevation of the bioactive form of TGFβ occurred in most patients during IL-2 therapy, it was significantly higher in patients with clinical regression of tumor (p =,004). In the first 2 weeks of therapy increase of plasma TGFP activity appeared to correlate with a decrease of platelet counts, suggesting that the factor may derive from the storage form of TGFβ contained therein.     

Origin of High-Grade Lymphomas in Richter Syndrome

Patients with B cell chronic lymphocytic leukemia (CLL) occasionally develop high-grade B cell lymphomas that are associated with constitutional symptoms, rapidly progressive lymphadenopathy, and swift clinical deterioration. Now known as Richter syndrome, this symptom complex develops in approximately 5% of all patients with CLL. Structural and molecular analysis of the immunoglobulin (Ig) genes have allowed investigators to define the clonal relationship between the leukemia and lymphoma cells of a given patient. In most cases the aggressive lymphoma evolves from the original leukemia cell clone. However, in some cases the lymphoma apparently represents a second malignancy. Differentiation between these two types of lymphoma may have clinical significance. Further investigation is required to allow for identification of CLL patients who are at risk for developing Richter syndrome and to understand factors involved in its etiopathogenesis.     

Cell kinetics of CD34-positive hematopoietic cells following chemotherapy plus colony-stimulating factors in advanced breast cancer

Bone-marrow (BM) hematopoietic precursors are recruited into proliferative activity when colony-stimulating factors (CSF) are sequenced with chemotherapy (CT). Previous studies suggested that further CT can be safely administered only when the increased proliferative activity of these cells has subsided, because most cytostatic drugs selectively damage cycling cells. The safest interval between CSF discontinuation and the start of the next CT course needs to be ascertained in vivo. Thirty patients with advanced breast cancer were treated with an intensified FEC regimen, planned at 21-day intervals, sequenced with granulocyte-macrophage (GM)-CSF (15 patients) or granulocyte (G)-CSF (15 patients). Using flow cytometry (FCM) we evaluated the proliferation kinetics of CD34⁺ BM hematopoietic progenitors before CT + CSF and at different times after CSF administration was stopped. FEC + GM- and FEC + G-CSF sequences both induced a rapid and sustained increase in the percentage of BM myeloid precursors (BMMP%) and in the cycling status of CD34+ BM cells. However, while the BMMP% remained elevated in both cases after CSF were stopped, the enhanced proliferative activity of CD34+ cells decreased more rapidly after GM- than after G-CSF. Using FCM, CD34⁺ BM-derived hematopoietic presursor cell kinetics is readily evaluated in the clinical setting. The administration of CSF following CT increases both the proliferative activity of CD34+ BM cells and the BMMP%. After CSF were discontinued a kinetic refractoriness of hematopoietic progenitors was more evident after GM-CSF than after G-CSF. These data may be of value in designing clinical trials to avoid cytostatic damage to the BM hematopoietic stem-cell compartment. © 1995 Wiley-Liss, Inc.     

Obstructive sleep apnoea probably related to a foreign body

A 2-year-old child was admitted because of sudden onset of symptoms compatible with obstructive sleep apnoea. Physical examination revealed slightly hypertrophic tonsils. A polygraphic study showed 150 apnoeic episodes of obstructive type during 8 h night sleep.A foreign body consisting of a piece of a celophane candy wrapper was found by surgery. Removal of the foreign body, the adenoids and tonsils resulted in a complete recovery. A second polygraphic study performed 4 months after surgery gave entirely normal results. A foreign body should be considered in the aetiology of obstructive sleep apnoea of sudden onset in children.Abbreviation OSA obstructive sleep apnoea     

Intracranial bleeding: epidemiology and relationships with antithrombotic treatment in 241 cerebral hemorrhages in Reggio Emilia

BACKGROUND AND OBJECTIVES: Anticoagulant (AC) and antiplatelet (AP) drugs are effectively used in the prevention of thromboembolic events, with the trade-off of bleeding side effects, particularly intracranial. The aim of this study was to determine the incidence of intracranial bleeding in the population of Reggio Emilia and to investigate the potential effect of AC and AP drugs. DESIGN AND METHODS: We reviewed all the patients admitted for cerebral hemorrhages to our hospital between April 1998 and September 2000. Data were collected with a standardized form. All the patients were followed-up to estimate long-term mortality. Chi(2) and t-tests were used as appropriate. Logistic regression analysis was performed to test predictors of mortality. Pharmaceutical department data were employed to estimate the total number of patients receiving AC and AP drugs. RESULTS: We found 241 cases (107/134 female/male, mean age 61 years, 133/107 spontaneous/traumatic events, 0.32/1,000/year overall). Twenty-nine and 47 of these patients were being given AC or AP drugs, respectively (4.9/1,000/year and 3.7/1,000/year). The relative risk of intracranial bleeding was 11.5 in AP and 15.3 in AC treated patients. Two patients (one underwent neurosurgery and one thrombolytic treatment) were excluded from mortality and risk factors analysis. Six patients were lost from follow-up and excluded from mortality analysis. Overall mortality was 100/233 (42.9%); mortality in traumatic events was 25/103 (24.2%) versus 75/130 (57.7%) in spontaneous events. Mortality was 19/29 (65.5%), 26/47 (55.3%) and 55/157 (35%) in AC recipients, AP recipients, and untreated patients, respectively. This increased risk was mainly confined to traumatic events (p = 0.06), without difference between AC and AP recipients. At the time of the event, the mean duration of oral AC treatment was 26.3 months (range 1-120). Mean INR was = 3.1 (range 1.6-8.8). Mortality was significantly predicted by the Glasgow Coma Scale Score (GCS) at admission (p < 0.0001), by the type of bleeding (spontaneous versus traumatic) (p = 0.0026), and by age (p < 0.0001). INTERPRETATION AND CONCLUSIONS: Careful selection of patients and prevention of traumatic events are the main candidate mechanisms to reduce intracranial bleeding in patients being treated with AC and AP drugs.     

N-acetylcysteine potentiates the antihypertensive effect of ACE inhibitors in hypertensive patients

Sulfhydryl group donors, such as N-acetylcysteine (NAC), may enhance the antihypertensive effect of some drugs through a nitric oxide (NO) mechanism. It has been observed that the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEIs) is, at least partially, mediated by NO. We performed a within patient crossover study with the aim to investigate the potential effect of NAC on the ACEI antihypertensive action, via an NO-dependent mechanism. We studied 18 smoker (> 10 years of habit and > 10 cigarettes daily) hypertensive patients (15 males and three females, aged 69 +/- 5 years) on ACEI therapy (11 captopril and seven enalapril). Patients were randomly allocated to two treatment arms. In one arm, the patients (n = 10) initially received the addition of NAC (600 mg t.i.d.) to the ACEI regimen. In the other group (n = 8), the patients remained only on ACEI. After 21 days, the therapeutic patterns were crossed. The first group received only ACEI, and the second group received ACEI and NAC and completed other 21-day treatment period. We evaluate the effect of NAC on each patient by ambulatory blood pressure monitoring (ABPM), performed at the end of each therapeutic regimen. A significant decrease in systolic and diastolic 24-h blood pressure (24 hBP) and daytime BP (dtBP) was achieved with the combination of ACEI and NAC (ACEI + NAC) when compared to the period with only ACEI: 24 hBP = 146.1 +/- 4.2 vs 137 +/- 3.1 (p < 0.05) and 89.2 +/- 2.8 vs 83.5 +/- 3.7mmHg (p = 0.01). DtBP: 149.7 +/- 5.6 vs 141 +/- 3.7 and 92.1 +/- 4 vs 86 +/- 3.2 (both, p < 0.05). No significant difference was observed in night-time BP (ntBP). The NAC effect was not statistically different for the two ACEIs. In conclusion, the addition of NAC to an ACEI potentiates its antihypertensive effect during 24hBP and dtBP in smoker hypertensives. This effect may be mediated by an NO-dependent mechanism, probably through the protective effect of NAC on NO oxidation.     

The saphenous vein: derivation of its name and its relevant anatomy.

Generally, when the origin of the word saphenous is discussed, most affirm that the term derives from the Greek word safaina, which means "evident." The ancient Greeks knew only the caudal portion of the vein, and neither the Greeks nor the Romans used the term saphena. In fact, the term first appeared in the writings of Avicenna. In contrast, the term saphenous is derived from the Arabic el safin, which means "hidden" or "concealed." Ancient Arabic physicians knew the anatomy of superficial veins of the human body and its extremities because they performed therapeutic bleeding. Arabic physicians phlebotomized the distal portion of the greater saphenous vein (GSV) at the ankle. Such phlebotomies were never performed on the proximal portions of the GSV because they were not superficial enough to be clearly evident. As a consequence, the proximal GSV was called el safin, or "the concealed." The modern reader will recognize that based on duplex examination, the GSV is correctly identified on the basis of its deep position with the superficial fascia covering it. This information may be useful in modern saphenous vein surgery in identifying the proximal portion of the GSV.     

Molecular genetics of primary congenital glaucoma in Brazil

PURPOSE: To determine the distribution of CYP1B1 gene mutations in Brazilian patients with primary congenital glaucoma (PCG). METHODS: PCG diagnosis was established by presence of buphthalmos in at least one affected eye and associated high intraocular pressures before the age of 3 years. CYP1B1 mutation screening of 52 patients with PCG was performed by SSCP and direct sequencing of PCR fragments. RESULTS: Eleven mutations, four of which are novel, were observed in 26 (50%) individuals. A new frameshift mutation (4340delG) was observed in 20.2% of all individuals screened. These individuals had early-onset, bilateral glaucoma that necessitated multiple surgical interventions. CYP1B1 mutations were twice as frequent in affected individuals of European descent as in individuals of African descent. Analysis of six intragenic single nucleotide polymorphisms (SNPs) established 5'-C-C-G-G-T-A-3' as the most common haplotype among the affected Brazilian individuals. A nonsense mutation (W57X) previously reported in an individual with Peters anomaly (compound heterozygote) was also observed in two individuals with PCG but combined with different mutations. A newly developed SSCP assay enabled us to detect all DNA mutations and polymorphisms previously detected by direct sequencing. CONCLUSIONS: Our results indicate that CYP1B1 mutations may be responsible for half of cases of PCG in the Brazilian population. The SNP haplotype 5'-C-C-G-G-T-A-3' was associated with the majority of CYP1B1 mutations. This haplotype harbors the high-activity V432 allele, which is emerging as a putative susceptibility factor in several cancers.