The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1.

In non-small cell lung cancer (NSCLC), receptor tyrosine kinases (RTKs) stand out among causal dominant oncogenes, and the ablation of RTK signaling has emerged as a novel tailored therapeutic strategy. Nonetheless, long-term RTK inhibition leads invariably to acquired resistance, tumor recurrence and metastatic dissemination. In ALK+ cell lines, inhibition of ALK signaling was associated with coactivation of several RTKs, whose pharmacological suppression reverted the partial resistance to ALK blockade. Remarkably, ERBB2 signaling synergized with ALK and contributed to the neoplastic phenotype. Moreover, the engagement of wild-type epidermal growth factor receptor or MET receptors could sustain cell viability through early growth response 1 (EGR1) and/or Erk1/2; Akt activation and EGR1 overexpression prevented cell death induced by combined ALK/RTK inhibition. Membrane expression of ERBB2 in a subset of primary naive ALK+ NSCLC could be relevant in the clinical arena. Our data demonstrate that the neoplastic phenotype of ALK-driven NSCLC relays 'ab initio' on the concomitant activation of multiple RTK signals via autocrine/paracrine regulatory loops. These findings suggest that molecular and functional signatures are required in de novo lung cancer patients for the design of efficacious and multi-targeted 'patient-specific' therapies.

High prevalence of thyroid dysfunction in pregnant women.

BACKGROUND/AIM: Maternal thyroid dysfunction during pregnancy has been associated with adverse obstetric and neonatal outcomes. This prospective study evaluates the prevalence of these disorders in pregnant women. SUBJECTS AND METHODS: Serum levels of TSH, free T4 (fT4), and thyroperoxidase antibodies (TPO-Ab) were measured in 951 women at different gestational ages of pregnancy. Trimester-specific reference ranges for TSH were used to classify pregnant women into five groups: 1) Overt hypothyroidism (OH); 2) Subclinical hypothyroidism (SCH); 3) Isolated hypothyroxinemia (IH); 4) Low TSH (isolated or associated with high fT4); and 5) Normal. A classification was made also according to the lower and upper ranges provided by the manufacturer for thyroid hormones. Pregnant women who were at a high risk of developing thyroid disease were identified. RESULTS: Altogether, 117 women (12.3%) had hypothyroidism and 25 (2.6%) had low TSH. The prevalence of both OH and SCH was higher in the high-risk group than in the low-risk group, but 17.9% of women with hypothyroidism were classified at low-risk. A family history of thyroid disorders and TPO-Ab positivity increased the risk of SCH. Using non-pregnant reference range for TSH, 10.6% of women were misclassificated. CONCLUSIONS: The high prevalence of hypothyroidism observed in this study suggests that accurate thyroid screening with trimester specific reference ranges should be warranted, particularly in areas with mild to moderate iodine deficiencies.

Effects of epidural analgesia on uterine artery Doppler in labour.

BACKGROUND: The effects of epidural anaesthesia on maternal uteroplacental blood flow in the presence of uterine contractions remain unclear. The aim of our study was to evaluate the effects of epidural analgesia with bolus doses on uterine artery pulsatility index (UtA-PI) during labour. METHODS: In a prospective case-control study, UtA-PI was measured during uterine contraction and relaxation in nulliparous women in active labour with (epidural group) and without (control group) epidural analgesia. Patients in the two groups were matched for gestational age at delivery, American Society of Anesthesiologists physical status score, and cervical dilatation at the beginning of labour. In the epidural group, an epidural catheter was placed after prehydration with 500 ml i.v. saline, and sufentanil 2 µg ml⁻¹ (5 ml) and ropivacaine 1 mg ml⁻¹ (20 ml) were administered. UtA-PI was measured before (T0), 30 min (T30), and 90 min (T90) after the first administration of epidural analgesic drugs, during both uterine relaxation and contraction. RESULTS: Fifty-two patients were included in the study, 33 in the epidural group and 19 in the control. UtA-PI was significantly higher in the epidural compared with the control group, only at T30 and during contraction. There were no differences in the rate of oxytocin augmentation, mode of delivery, birth weight, and umbilical artery pH between the two groups. CONCLUSIONS: Epidural analgesia using ropivacaine 1 mg ml⁻¹ (20 ml) significantly reduced placental blood flow only transiently during uterine contraction 30 min after the injection. These changes did not seem to affect neonatal outcomes.

Nuclear shape in papillary thyroid carcinoma: a role for lamin B receptor?

Irregularity in the nuclear shape, with extensive folds and invaginations of the nuclear membrane (NM), remain the basic diagnostic feature of papillary thyroid carcinoma (PTC). The biological reasons for these irregularities are obscure, but evidence has been presented that they might be linked to RET÷PTC gene translocation. In the present study, we have investigated the hypothesis that the NM irregularities in PTC might be linked to alterations in the expression of lamin B receptor (LBR), a component of the inner NM responsible for the distribution of Lamin B and associated chromatin. Fisher AH et al. already reported on the lack of LBR in PTC, a finding in contrast with the observation that a reduced expression of LBR because of gene mutation is responsible for the lack of nuclear segmentation of granulocytes in Pelger-Huët anomaly. In the present study, we confirmed the lack of immunohistochemical staining for LBR in PTC nuclei, in contrast to a positive staining in intestinal epithelium and stromal cells. However, Western blot and RT-PCR analysis demonstrated a strongly positive reaction in PTC extracts, thus proving an expression of LBR higher in PTC cases and cells than in follicular carcinoma cells. In conclusion, our data suggest that LBR is heavily expressed in PTC cells, but an abnormal folding of the protein might explain its lack of immunohistochemical reactivity and be associated with the anomalous folding of the NM.

Impact of laryngeal mask airway and tracheal tube on pulmonary function during the early postoperative period.

BACKGROUND: The tracheal tube (TT) produces reversible bronchoconstriction and increases pulmonary airway resistance compared to the laryngeal mask airway (LMA). The possible persistence of this effect in the postoperative period has not been studied. The aim of this study was to compare the early postoperative pulmonary function in healthy patients undergoing minor surgical procedures with the LMA or with the TT. METHODS: Sixty patients scheduled for saphenous vein stripping under general anaesthesia were randomised to receive the LMA or the TT. Before anaesthesia and 20 min after LMA or TT removal, pulse oxymetry values (SpO(2)) were recorded and patients performed forced spirometry in the supine position. RESULTS: Preoperative pulmonary function was normal in both groups. There were no differences between groups in the preoperative respiratory function test and SpO(2). Following surgery SpO(2), forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF) decreased in both groups. The FEV1/FVC did not change in either of the groups. In the TT group, compared to patients using the LMA, there was a greater relative decrease of SpO(2) (2.7 +/- 2.7% vs. 1.3 +/- 2.2%, P=0.017), FEV1 (17.6 +/- 12.2% vs. 8 +/- 17.4%, P=0.008), FVC (15.8 +/- 12.4% vs. 9 +/- 13.4%, P=0.023) and PEF (20.6% +/- 15.3% vs. 8.1 +/- 33.3%, P=0.033). CONCLUSIONS: This study demonstrates greater early postoperative respiratory restrictive syndrome and lower arterial oxygen saturation following tracheal intubation compared to LMA use in patients without respiratory disease.

Acute quadriplegia with delayed onset and rapid recovery. Case report.

The authors describe a patient with severe head injury and sepsis who became acutely quadriplegic 3 days postinjury because of a critical illness polyneuropathy (CIP) and critical illness myopathy (CIM), which resolved rapidly after treatment of the underlying infection. In only 3 days the patient developed septic shock together with flaccid quadriplegia and absent deep tendon reflexes with no clinical or radiological evidence of central nervous system deterioration. Neurophysiological studies showed an acute axonal sensorimotor polyneuropathy, whereas the clinical course strongly suggested a concurrent myopathy. A severe Staphylococcus epidermidis infection accompanied by bacteremia was treated and the patient recovered fully within a few days. Although the case described here is unique because of its very early onset and rapid resolution, CIP and CIM are frequent complications of sepsis and multiple organ failure. The authors suggest that severely head injured patients with sepsis should be evaluated for CIP and CIM when presenting with unexplained muscle weakness or paralysis.

Critical illness myopathy and neuropathy.

BACKGROUND: Critically ill patients may develop muscle weakness or paralysis during the course of sepsis and multiple-organ failure. We studied peripheral nerve and muscle disorders (NMD) in comatose patients. METHOD: Comatose patients who developed paralysis associated with absent deep-tendon reflexes had electroneuromyography (ENMG) and muscle-nerve biopsy specimens taken. Onset and duration of sepsis, multiple-organ dysfunction and failure, biochemical alterations, and drugs potentially interfering with nerve-muscle function were recorded. FINDINGS: 24 patients became quadriparetic or quadriplegic; muscle changes were found in 23. Axonal neuropathy was found in eight of 22 patients examined. All patients had prolonged sepsis and multiple-organ dysfunction, but only 14 had multiple-organ failure. Drugs such as steroids, neuromuscular-blocking agents, and aminoglycosides were not responsible for paresis, and the part played by hyperglycaemia and hypoalbuminaemia is uncertain. Attending physicians predicted a fatal outcome in all cases, although six of seven survivors fully recovered within 115-210 days from the onset of paralysis. INTERPRETATION: Comatose patients may become completely paralysed because of NMD. The diagnosis is important to avoid unnecessary investigations and unreasonably pessimistic prognosis. ENMG is essential for the diagnosis and for planning further clinical management. Biopsy needs to be done only when it is necessary to properly classify NMD.

Failure of GnRH analogue to inhibit serum concentrations of testosterone and 17 alpha-hydroxyprogesterone in hCG-substituted hypogonadotropic hypogonadism.

Gonadotropin-releasing hormone analogues (GnRH-A) induce inhibition of testicular function and reduction of serum testosterone (T) in man, but the mechanism involved is still debatable. To elucidate it we studied six patients with hypogonadotropic hypogonadism (HH) in chronic substitution with hCG for correction of androgen deficiency symptoms, and evaluated the effect of addition of GnRH-A to the hCG therapy on plasma levels of T and 17 alpha-hydroxyprogesterone (17 OHP). All patients were treated with 1000 U of hCG in every 3rd day for 24 weeks. After 8 weeks of this regimen, GnRH-A, Buserelin (D-Ser-TBU-EA-LHRH), 200 micrograms per day sc, was added and given for 8 weeks. After cessation of analogue administration patients were followed for 8 further weeks. The levels of the two steroids did not differ markedly in the pre- and post-GnRH-A period. GnRH-A given for two months did not lower T or 17 OHP levels as in eugonadal men after similar treatment. The median T concentrations during GnRH-A tended to be increased, with plasma values higher (P less than 0.025) than the peak values observed during hCG alone. Since administration of Buserelin did not inhibit hCG-sustained steroid levels in these HH patients, it is conceivable that GnRH-A may have lacked a direct inhibitory gonadal effect in such experimental conditions.