miR-194-5p/BCLAF1 deregulation in AML tumorigenesis.

This corrects the article DOI: 10.1038/leu.2017.64.

Prognosis of isolated acute post-traumatic subdural haematoma.

AIM: Acute subdural haematoma (ASDH) is seldom an isolated lesion and it is difficult to understand the mechanisms which determine the poor prognosis associated to this occurrence. Aim of this study was estimating the outcome of patients with ASDH without any companion lesions by analysing the haematoma volume, its thickness and midline shift. METHODS: Twenty-eight severely head injured patients (Glasgow Coma Scale, GCS =/<8) with isolated unilateral ASDH admitted in intensive care unit (ICU) were retrospectively studied. The haematoma thickness, the midline shift, the ASDH volume were obtained from the first emergency computerized tomography (CT) scan and analysed by a computer assisted programme (Osiris). Patients' outcome was scored according to the Glasgow Outcome Scale (GOS) 6 months after the event. According to their GOS the patients were further divided in 2 groups (favourable outcome: GOS 4-5, poor outcome: GOS 1-2-3). RESULTS: Midline shift ranged from 0 to 19.2 mm; we found a larger midline shift in those patients who died and in patients with severe disability or vegetative state 6 months after the trauma. CONCLUSION: The presence and size of midline shift was a more important determinant of outcome than ASDH volume or its thickness.

miR-194-5p/BCLAF1 deregulation in AML tumorigenesis.

Deregulation of epigenetic mechanisms, including microRNA, contributes to leukemogenesis and drug resistance by interfering with cancer-specific molecular pathways. Here, we show that the balance between miR-194-5p and its newly discovered target BCL2-associated transcription factor 1 (BCLAF1) regulates differentiation and survival of normal hematopoietic progenitors. In acute myeloid leukemias this balance is perturbed, locking cells into an immature, potentially 'immortal' state. Enhanced expression of miR-194-5p by treatment with the histone deacetylase inhibitor SAHA or by exogenous miR-194-5p expression re-sensitizes cells to differentiation and apoptosis by inducing BCLAF1 to shuttle between nucleus and cytosol. miR-194-5p/BCLAF1 balance was found commonly deregulated in 60 primary acute myeloid leukemia patients and was largely restored by ex vivo SAHA treatment. Our findings link treatment responsiveness to re-instatement of miR-194-5p/BCLAF1 balance.

High levels of tyrosine phosphorylated proto-ret in sporadic phenochromocytomas.

Pheochromocytomas are tumors originating from chromaffin cells, the large majority of which are sporadic neoplasms. The genetic and molecular events determining their tumorigenesis continue to remain unknown. On the other hand, RET germ-line mutations cause the inheritance of familial tumors in multiple endocrine neoplasia (MEN)-2 diseases, which account for a minority of pheochromocytomas. We investigated the expression of the RET gene in 14 sporadic tumors harboring no activating mutations. A subset of highly RET-expressing tumors (50%) could be distinguished. They showed RET transcript, protein amounts as well as Ret-associated phosphotyrosine levels similar to those measured in MEN-2A-associated pheochromocytomas. We also determined the GDNF and GDNF family receptor alpha (GFRalpha)-1 transcript levels in tumors and in normal tissues. Whereas the GFRalpha-1 transcripts were detected at similar levels in normal tissues and in tumors, GDNF was frequently found expressed in sporadic tumors at levels several times higher than in controls. These results led us to propose the existence of an autocrine or paracrine loop leading to chronic stimulation of the Ret signaling pathway, which could participate in the pathogenesis of a number of sporadic pheochromocytomas.

Goiter size and thyroid function in an endemic goiter area in northern Italy.

Thyroid function was studied in a large number of subjects residing in Varsi, a town in the province of Parma, Italy. In this area, endemic goiter associated with moderate iodine deficiency [59 +/- 3 (+/- SE) microgram iodine/g creatinine], as defined by WHO criteria, affects 65% of the population. Serum T4, T3, thyroglobulin (Tg), and TSH concentrations were measured by RIA in 1218 subjects. The TSH response to TRH was determined in 108 subjects selected randomly from the groups with different grades of goiter. No significant change in serum T4 concentrations was found in subjects with different grades of goiter. Serum T3 concentrations were higher in subjects with the larger goiters. Serum Tg concentration progressively increased, and serum TSH progressively decreased with increasing goiter size. The TSH response to TRH was diminished in subjects with larger goiters. The findings of decreasing serum TSH concentrations and blunted TSH responses to TRH as goiter size increased suggest the possibility of autonomous thyroid function in the larger goiters in subjects residing in this area of moderate iodine deficiency.

Failure of metoclopramide to affect thyrotropin concentration in the term human fetus.

Metoclopramide (MET), a potent dopamine receptor-blocking drug, or saline was administered to 125 term pregnant women at various time intervals (5-412 min) before delivery. Maternal serum was obtained before and after MET injection. Cord blood was obtained at delivery in MET-treated and saline-treated (control group) women. No significant changes in serum TSH, T4, T3, or rT3 concentrations were observed in maternal or cord blood after MET administration. These results suggest that, in contrast to euthyroid nonpregnant women and men, MET administration does not induce a rise in serum TSH concentration in term pregnant women or in the term fetus. Thus, the dopaminergic inhibitory effect on anterior pituitary TSH secretion may not be an important factor in TSH regulation during pregnancy or in the fetus, or the dose of MET employed may be unable to overcome the dopamine inhibitory effect.

Lack of seasonal variation in abnormal TSH secretion in patients with seasonal affective disorder.

The circadian variations in thyroid-stimulating hormone (TSH) secretion, with particular attention to the nocturnal serum TSH surge and the TSH response to thyrotropin releasing hormone (TRH), were measured in seven patients with seasonal affective disorder (SAD) and in eight normal controls. Both patients with SAD and normal controls were tested in fall/winter, when patients were suffering depressive symptoms, and in spring/summer, when patients were euthymic. The TRH tests were performed in the morning. In all tests, the mean peak TSH response to TRH was significantly lower in the patients with SAD than in the normal controls. No significant differences were observed in either group between spring/summer and fall/winter tests. At both periods, patients with SAD showed normal TSH levels in the morning, but did not experience a nocturnal TSH surge. In this group, morning and night TSH levels were similar. In contrast, normal controls showed significantly higher TSH levels at night than in the morning. Serum-free thyroid hormone levels were in the normal range in all subjects. Morning and night serum cortisol levels and 24-hour urinary cortisol concentrations were similar in all subjects. These data show that the secretion of TSH is impaired in SAD, regardless of the phase of the psychiatric disease. The low TSH response to TRH in the presence of normal serum thyroid hormone levels and the lack of the TSH nocturnal surge suggest that patients with SAD might be affected by mild central hypothyroidism.

Luteinizing hormone and cortisol responses to naloxone in normal weight women with bulimia.

The present study was undertaken in order to establish whether alterations in the endogenous opioid control of luteinizing hormone (LH) and ACTH/cortisol secretion occur in bulimic women with normal body weight and normal menstrual cycles. For this purpose, the capability of the opioid antagonist naloxone (4 mg injected as an intravenous bolus at time 0, plus 10 mg infused over 2 hr) to increase the circulating levels of LH and cortisol was tested in nine bulimic women and in nine age- and weight-matched normal controls. All women were tested on the 22nd day of a normal menstrual cycle. Two days later, a control test with normal saline (NaCl 0.9%) instead of naloxone was performed. The basal levels of LH and cortisol were similar in the bulimic and normal subjects and were not modified by the administration of normal saline. In contrast, the administration of naloxone significantly increased plasma LH and cortisol levels in all subjects, with peak LH responses at 30 min and peak cortisol responses at 60 min. The naloxone-induced LH and cortisol increases were significantly higher in the bulimic women than in the normal controls. These data indicate the presence of an increased opioid inhibitory tone in the control of LH and ACTH/cortisol secretion in normal weight bulimic women with normal menstrual cycles.

Naloxone decreases the inhibiting effect of ethanol on the release of arginine-vasopressin induced by cigarette smoking in man.

In order to establish whether ethanol exerts its inhibiting effect on the nicotine-induced release of arginine-vasopressin (AVP) by interacting with an opioid pathway, six normal volunteers were treated with naloxone (2 or 4 mg as IV bolus, plus 5 or 10 mg infused over 105 minutes) during (2 nonfilter) cigarette smoking and ethanol (50 mL to 110 mL of whiskey) drinking. In addition, control experiments with naloxone, ethanol, or cigarette smoking alone were performed. When given alone, naloxone and ethanol did not modify AVP secretion, whereas nicotine increased plasma AVP levels by about 2.5-fold. This effect was completely blocked by ethanol. In the presence of naloxone, AVP rose only by about 1.7-fold in response to nicotine. Since naloxone only partially reversed the inhibiting effects of ethanol, only a partial involvement of opioid peptides in ethanol action might be supposed. Alternatively, ethanol and naloxone-sensitive opioids might produce their inhibiting effects on AVP rise in response to nicotine through independent pathways.

Basal and glucose- and arginine-stimulated serum concentrations of insulin, C-peptide, and glucagon in hyperthyroid patients.

The effect of oral glucose and arginine infusion on plasma glucose, glucagon, serum insulin, and C-peptide concentrations was evaluated in 16 patients with hyperthyroid Graves' disease and in ten euthyroid age- and sex-matched normal subjects. Basal plasma glucose concentrations were significantly higher in the hyperthyroid patients, but the plasma glucose response following glucose and arginine administration was similar in the two groups. The insulin response was similar in the hyperthyroid and normal subjects after glucose administration and significantly lower during arginine infusion in the hyperthyroid patients. The serum C-peptide response to both glucose and arginine administration was markedly blunted in the hyperthyroid patients, and the plasma glucagon response to arginine infusion was decreased. These results suggest that pancreatic beta and alpha cell secretory function is impaired in hyperthyroidism as assessed by C-peptide and glucagon secretion following oral glucose administration and arginine infusion. The apparent discrepancy between C-peptide and insulin secretion in the hyperthyroid patients following glucose administration might be due to diminished hepatic extraction of insulin or enhanced metabolism of C-peptide.

Effect of estrogen or insulin-induced hypoglycemia on plasma oxytocin levels in bulimia and anorexia nervosa.

Plasma oxytocin (OT) levels were measured before and after stimulation with estrogens (1 mg ethynylestradiol orally) or with insulin (0.15 IU/kg)-induced hypoglycemia in seven underweight women with anorexia nervosa, eight normal weight bulimic women, and nine normal controls. Anorectic patients were amenorrhoic; they were tested at their first hospitalization (first tests) and again 8 to 9 weeks later (second tests) when they were eating normally, but were still at a low weight. In addition, anorectic women were tested 16 to 17 weeks after the first test (third tests), when their weight was restored to normal. Normal and bulimic women were tested on the fourth days of normal menstrual cycles. Insulin induced similar hypoglycemic responses in all groups. At each time point of the estrogen tests, plasma estrogen levels were similar in bulimic and normal women, whereas they were significantly lower in anorectic subjects. There were no differences in the basal levels of OT among groups. Both insulin-induced hypoglycemia and estrogen treatment produced striking OT increments in bulimic and control women, without significant differences between groups. During the first tests, no significant increase in plasma OT levels was observed in underweight anorectic women in response to both releasing stimuli. After partial weight recovery, the anorectic women showed a slight, but significant, increase in the OT responses to both insulin-induced hypoglycemia and estrogen administration. Both hypoglycemia- and estrogen-induced OT increases observed during the second tests were significantly lower in underweight anorectic patients than in normal controls. Anorectic subjects regained normal OT responsiveness to both stimuli after complete weight recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

HPV detection and p53 alteration in squamous cell verrucous malignancies of the lower genital tract.

We examined five cases of verrucous carcinoma (VC) and two cases of giant condyloma of Buschke-Löwenstein (GCBL) associated with invasive squamous cell carcinoma (ISCC), by immunocytochemistry and molecular techniques. Neither human papillomavirus (HPV) footprints nor p53-altered expression and/or mutation were observed among the cases of VC. By contrast, both cases of GCBL with ISCC turned out to be HPV 6 or 11 positive, showed overexpression of p53 and, one of the two, a mutation in the nucleotide sequence of this tumor suppressor gene. The results point out that VC and GCBL with ISCC, in spite of some morphologic similarities, are two distinct entities, the former being unrelated to both HPV and p53 inactivation and the latter related to both. Regarding p53, immunocytochemical and molecular data on GCBL with ISCC suggest a role of mutant p53 in the progression of malignancy into invasion.

Papillomavirus, p53 alteration, and primary carcinoma of the vulva.

Twenty-nine samples from 28 cases of vulvar squamous cell carcinoma, of which 13 fulfilled the criteria of the bowenoid subtype (mean age 45 years, range 31-68) and 16 of the usual subtype of invasive squamous cell carcinoma (ISCC) (mean age 67.5 years, range 34-83) were investigated for human papillomavirus (HPV) DNA, TP53 alterations, and mdm2 and bcl-2 gene product deregulation. Microscopically all the bowenoid subtype cases (group I) showed a high-grade intraepithelial (VIN 3, carcinoma in situ) lesion associated with early invasive carcinoma in six cases and overt invasive carcinoma in one. By contrast, no evidence of early carcinoma was present in the ISCCs (group II). By in situ hybridization and/or Southern blot hybridization or polymerase chain reaction (PCR), HPV DNA was detected in all cases of group I and in four of 16 cases (25%) of group II, two only by Southern blot after PCR. By single-strand conformation polymorphism and immunocytochemistry only wild-type TP53 and absence of detectable p53 product, respectively, were found in all cases of group I, i.e., in high-risk HPV-positive carcinomas, whereas mutations and/or p53 overexpression accounted for 75% in group II, i.e., in mainly HPV-negative carcinomas. The TP53 gene mutations observed in invasive carcinomas were significantly related to node-positive cases (p = 0.04). Taken together and in agreement with in vitro data, these results support the view that an alteration of TP53, gained either by interaction with viral oncoproteins or by somatic mutations, is a crucial event in the pathogenesis of vulvar carcinomas, but that TP53 mutations are mainly associated with disease progression. Finally, a preliminary immunocytochemical analysis seems to speak against the possible involvement of both MDM2 and BCL-2 gene products in the development of vulvar carcinoma.

Simultaneous in situ hybridization for DNA and RNA reveals the presence of HPV in the majority of cervical cancer cells.

Thirteen cases of invasive squamous cell carcinoma of the uterine cervix containing HPV types 16 or 18 DNA sequences, as detected by Southern blot analysis, were investigated by in situ hybridization on routine paraffin sections, using 35S nick-translated DNA probes. Simultaneous in situ hybridization for DNA and RNA showed that in ten out of 13 cases (77%) the percentage of tumor cells containing HPV 16 or 18 varied from 75 to 100%. In one case, harboring both in situ and invasive carcinoma, the same type of HPV DNA was detected in both components. This finding suggests that neoplastic cells retained the viral genome during progression to invasiveness.

Molecular cytogenetics and its applications to soft tissue tumor analysis.

Cytogenetic analyses have demonstrated the association of specific chromosomal changes with particular types of soft tissue tumors. This work describes the molecular cytogenetic approaches to genetic analysis of these tumors. It illustrates how molecular cytogenetics may provide a rapid and sensitive method of diagnosis and can contribute to identify specific genes implied in the aetiology of soft tissue tumors.

Outcomes in abdominal hysterectomy patients with benign disease. Use of physician-developed clinical protocols.

OBJECTIVE: To develop a clinical protocol for standardizing preoperative and postoperative care in abdominal hysterectomy patients with benign disease while maintaining quality and increasing efficiency. STUDY DESIGN: Protocol and nonprotocol groups of patients were compared with respect to key quality and efficiency outcomes in a non-randomized study. Patient group outcomes were compared using descriptive, Student's t, chi 2 and log-rank statistics. Statistical tests were performed at a .05 level of significance. RESULTS: Results from two separate protocol study periods conducted in 1996 and 1997 are reported. In both study periods statistical analyses and graphic presentations illustrate that protocol implementation improved quality of care by increasing the percentage of patients receiving appropriate antibiotic prophylaxis; maintained quality as monitored through 30-day readmission rates and a postdischarge patient survey; and improved efficiency, as evidenced by shorter times to incision and length of hospital stay. CONCLUSION: At Toledo Hospital, the clinical practice protocol directed at abdominal hysterectomy patients has been an effective tool in efforts to improve quality and efficiency in patient care.

Medically complex pregnancy: a case report illustrating CNM/MD collaborative management.

In contemporary society, many women with complex medical conditions are attempting fertility and becoming pregnant. The patient presents with an impressive medical complication, yet many of her key educational and psychosocial needs are typical of those for any pregnant woman. Striving for "normalcy," she may actively seek midwifery care to help her create a family-centered birth experience. Indeed, the midwife practicing with physician colleagues may have the opportunity to collaboratively manage increasingly complex cases. This article describes the case of collaborative management during pregnancy and delivery of a patient with the cardiac syndrome Wolff-Parkinson White syndrome (WPW). First diagnosed with WPW at the age of 13, the patient's condition was initially controlled with oral medication. Eventually, the patient's symptomology worsened and required repeated treatment by cardiac ablation of the accessory pathway. Illustrative of the possibilities for enhanced care of the medically complex pregnant patient via collaborative management, the discussion details not only the pertinent physiologic events but the benefits and process of care. A review of the cardiophysiology of WPW is also presented.

[Low-malignancy duodenal leiomyosarcoma]. / Il leiomiosarcoma duodenale a bassa malignità.

The authors report a case of duodenal leiomyosarcoma presenting a low degree of histological malignancy. The main anatomoclinical features of the neoplasm are summarized. The authors conclude indicating not aggressive surgical therapy as adequate in such cases. However, a prolonged post-operative follow-up is always necessary, in order to detect recurrences as early as possible.

[Endoscopic insertion of a prosthesis in the palliative treatment of tumors of the head of the pancreas]. / L'apposizione di protesi per via endoscopica nel trattamento palliativo dei tumori della testa del pancreas.

The Authors report their experience of biliary endoscopic endoprosthesis placement in 42 patients for palliative treatment of carcinoma of the pancreatic head. The morbidity, the mortality and the duration of hospitalization are considerably less than with surgical biliodigestive anastomosis. The mean survival is almost the same in both cases.

Role of cytosolic calcium-dependent phospholipase A2 in Alzheimer's disease pathogenesis.

Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aß) fragments is well established although still more elusive are the molecular events of the cascade that from the Aß accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.