Successful use of dupilumab for the treatment of atopic dermatitis on the genitals, a neglected anatomical site.

Atopic dermatitis (AD) is a chronic inflammatory disease that may involve any cutaneous site; involvement of the genital area may greatly impair patients' quality of life but, as the inspection of genitals is not usually conducted during the routine physical examination of patients with AD, the genital presentation of AD is frequently neglected and under-reported. We decided to evaluate the incidence of genital AD in patients with moderate-severe AD and the relative response to anti-interleukin (IL)-4/IL-13 dupilumab. In our study, a high incidence of genital AD emerged but the use of dupilumab allowed a generalized improvement.

Optical force decoration of 3D microstructures with plasmonic particles.

Optical forces are used to push and aggregate gold nanorods onto several substrates creating surface-enhanced Raman scattering (SERS) active hot spots for Raman-based identification of proteins. By monitoring the increase of the protein SERS signal, we observe different aggregation times for different curvatures of the substrates. The slower aggregation dynamics on curved surfaces is justified by a simple geometrical model. In particular, this technique is used to decorate three-dimensional microstructures and to quickly realize hybrid micro/nanosensors for highly sensitive detection of biological material directly in a liquid environment.

Investigation of the

This Letter reports a study of the highly debated ^{10}Li structure through the d(^{9}Li,p)^{10}Li one-neutron transfer reaction at 100 MeV. The ^{10}Li energy spectrum is measured up to 4.6 MeV and angular distributions corresponding to different excitation energy regions are reported for the first time. The comparison between data and theoretical predictions, including pairing correlation effects, shows the existence of a p_{1/2} resonance at 0.45±0.03 MeV excitation energy, while no evidence for a significant s-wave contribution close to the threshold energy is observed. Moreover, two high-lying structures are populated at 1.5 and 2.9 MeV. The corresponding angular distributions suggest a significant s_{1/2} partial-wave contribution for the 1.5 MeV structure and a mixing of configurations at higher energy, with the d_{5/2} partial-wave contributing the most to the cross section.

Optical trapping of silver nanoplatelets.

Optical trapping of silver nanoplatelets obtained with a simple room temperature chemical synthesis technique is reported. Trap spring constants are measured for platelets with different diameters to investigate the size-scaling behaviour. Experimental data are compared with models of optical forces based on the dipole approximation and on electromagnetic scattering within a T-matrix framework. Finally, we discuss applications of these nanoplatelets for surface-enhanced Raman spectroscopy.

Optical trapping and optical force positioning of two-dimensional materials.

In recent years, considerable effort has been devoted to the synthesis and characterization of two-dimensional materials. Liquid phase exfoliation (LPE) represents a simple, large-scale method to exfoliate layered materials down to mono- and few-layer flakes. In this context, the contactless trapping, characterization, and manipulation of individual nanosheets hold perspectives for increased accuracy in flake metrology and the assembly of novel functional materials. Here, we use optical forces for high-resolution structural characterization and precise mechanical positioning of nanosheets of hexagonal boron nitride, molybdenum disulfide, and tungsten disulfide obtained by LPE. Weakly optically absorbing nanosheets of boron nitride are trapped in optical tweezers. The analysis of the thermal fluctuations allows a direct measurement of optical forces and the mean flake size in a liquid environment. Measured optical trapping constants are compared with T-matrix light scattering calculations to show a quadratic size scaling for small size, as expected for a bidimensional system. In contrast, strongly absorbing nanosheets of molybdenum disulfide and tungsten disulfide are not stably trapped due to the dominance of radiation pressure over the optical trapping force. Thus, optical forces are used to pattern a substrate by selectively depositing nanosheets in short times (minutes) and without any preparation of the surface. This study will be useful for improving ink-jet printing and for a better engineering of optoelectronic devices based on two-dimensional materials.

The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia.

DNA from 135 patients with chronic myelogenous leukemia (CML) at various clinical stages and Philadelphia (Ph1) chromosome positive acute lymphoblastic leukemia was investigated for alterations in a variety of proto-oncogenes which have been implicated in the evolution of CML from its chronic phase to blast crisis. The most common genetic change found in the evolution of typical Ph1 chromosome positive CML to blast crisis was an alteration of the p53 gene involving either a rearrangement, a deletion, or a point mutation in the coding sequence of the gene. Alterations of the p53 gene were found in the myeloid and the rare megakaryocytic variant of blast crisis but were absent in the lymphoid leukemic transformants. Gross structural alterations were seen in 11 of 54 (20%) of myeloid or unknown phenotypes of blast crisis and in only 1 of 44 chronic phase cases. Eight examples of mutations in the open reading frame of the p53 gene at codons 49, 53, 60, 140, 202, 204, 238, and 239 were observed in blast crisis patients. Mutations in the N-RAS gene were rare in typical blast crisis (2 of 27 cases) but were found in megakaryocytic and Ph1 negative myeloid blast crisis. We concluded that heterogeneous alterations in the p53 gene and occasionally in the N-RAS genes accompany the evolution of chronic phase CML to blast crisis.

A solid-phase radioimmunoassay for human prostatic acid phosphatase.

A solid-phase technique for radioimmunoassay of human prostatic acid phosphatase (EC 3.1.3.2) is described. Human prostatic acid phosphatase was purified from prostatic fluid. Monospecific antisera to the purified acid phosphatase were produced in rabbits. Disposable polypropylene tubes were coated with antiserum and used for radioimmunoassay with 125I-acid phosphatase. The nonspecific binding was minimized by saturating the binding sites of the tubes with bovine serum albumin. The working range of the technique was 1 to 30 ng of antigen. The solid-phase radioimmunoassay is rapid, sensitive, and efficient. In preliminary clinical trials it was shown that (a) patients with advanced prostatic cancer had elevated prostatic acid phosphatase levels by both enzymatic assay and radioimmunoassay assays, and (b) patients with other cancers were in the normal range for prostatic acid phosphatase.

Isozymes of acid phosphatase in normal and cancerous human prostatic tissue.

The supernatants of the homogenates from normal and cancerous human prostatic tissue run on polyacrylamide gel electrophoresis have 2 major electrophoretic bands when stained for prostatic acid phosphatase. The ratios of the electrophoretically distinguishable isoenzymes differ in normal and cancerous tissues. Similar distinctions between isoenzymes in normal and cancerous prostates are observed following column chromatographic separation or isoelectric focusing. The faster electrophoretic band can be separated by diethylaminoethyl cellulose column chromatography or by isoelectric focusing into at least five fractions with different electrophoretic mobilities. We could not find any differences in normal and cancerous tissues among these subfractions of the faster-moving electrophoretic band. Analysis by gel electrophoresis does not show association between these fractions after chromatographic or isoelectric separation of the prostatic acid phosphatase fractions. Quantitative, but no qualitative, differences in prostatic acid phosphatase isozymes occur in normal versus cancerous prostates.

Signatures of the Giant Pairing Vibration in the 14C and 15C atomic nuclei.

Giant resonances are collective excitation modes for many-body systems of fermions governed by a mean field, such as the atomic nuclei. The microscopic origin of such modes is the coherence among elementary particle-hole excitations, where a particle is promoted from an occupied state below the Fermi level (hole) to an empty one above the Fermi level (particle). The same coherence is also predicted for the particle-particle and the hole-hole excitations, because of the basic quantum symmetry between particles and holes. In nuclear physics, the giant modes have been widely reported for the particle-hole sector but, despite several attempts, there is no precedent in the particle-particle and hole-hole ones, thus making questionable the aforementioned symmetry assumption. Here we provide experimental indications of the Giant Pairing Vibration, which is the leading particle-particle giant mode. An immediate implication of it is the validation of the particle-hole symmetry.

The relationships of free to conjugated normetanephrine in plasma and spinal fluid of hypertensive patients.

The concentrations of free and total normetanephrine (NMN) were determined in the plasma of normotensives and patients with primary hypertension and pheochromocytoma. NMN values were measured in the cerebrospinal fluid (CSF) of patients. Free and conjugated NMN, the latter after acid hydrolysis, were assayed using S-adenosylmethionine in the presence of phenylethanolamine-N-methyltransferase to form labeled metanephrine. The conjugates of NMN were present in plasma as sulfates principally, as they were also liberated with arylsulfatase. Free and conjugated NMN levels were 117 +/- 10 and 1417 +/- 109 ng/liter, respectively in plasma of normotensives. The mean ratio of the content of conjugated to free NMN was 14.9 +/- 1.8 (mean +/- SEM). The contents of free and conjugated NMN were 155 +/- 33 and 1670 +/- 320 ng/liter in primary hypertensives, respectively, and the ratio of conjugated to free NMN was 18.5 +/- 3.3. These values did not differ significantly from those in normotensives. The contents of free and total NMN in the plasma of patients with pheochromocytoma were 50- to 60-fold greater than values in normotensive and primary hypertensives. The mean ratio of conjugated to free NMN in the plasma of patients with pheochromocytoma was similar to those in normotensives and primary hypertensives. The contents of free and conjugated NMN in the CSF of patients with pheochromocytoma exceeded those in primary hypertensives (P less than 0.01 and P less than 0.001). Further, the ratio of conjugated to free NMN in CSF was increased in patients with pheochromocytoma (33.9 +/- 8.1) compared to that primary hypertensives (8.3 +/- 2.3; P less than 0.001). The measurement of NMN in plasma and CSF may help characterize sympathetic nerve tone in patients with primary hypertension to elucidate the pathophysiology of the elevated blood pressure.

Effects of clonidine on central and peripheral nerve tone in primary hypertension.

To define the mechanisms whereby clonidine lowers blood pressure, we measured cerebrospinal fluid and plasma levels of norepinephrine, normetanephrine, epinephrine, dopamine, and the dopamine metabolite homovanillic acid in 10 primary hypertensive subjects before and after 3 months of clonidine treatment (mean dose, 0.68 mg/day). Catecholamines were measured by radioenzymatic methods. Cerebrospinal fluid and plasma sampling was performed after subjects had fasted and remained supine overnight, and plasma sampling was repeated 2 hours later, after subjects had ambulated. Supine and upright blood pressure fell, as might be expected. Cerebrospinal fluid levels of norepinephrine and normetanephrine fell significantly, but dopamine and homovanillic acid levels were unchanged. Plasma norepinephrine, normetanephrine, and epinephrine levels decreased 30 to 50%, and supine dopamine levels also fell. The percent fall in supine blood pressure was related to the fall of cerebrospinal fluid and plasma norepinephrine. There were also positive relationships between the decreases of plasma norepinephrine and of normetanephrine and dopamine. The cerebrospinal fluid/plasma norepinephrine ratio was unaffected by clonidine, suggesting that the drug lowered both pools equally. Our findings indicate that clonidine decreases both central and peripheral norepinephrine activity. The dopaminergic activity of cerebrospinal fluid was unaffected by clonidine, and though plasma dopamine levels tended to be lower after treatment, mean plasma prolactin level, an index of dopaminergic activity, was also unchanged. The fall in plasma epinephrine level is probably related to diminished sympathetic adrenomedullary stimulation and is unlikely to contribute to clonidine's antihypertensive action. These results also suggest that measurement of normetanephrine in cerebrospinal fluid and plasma provides a good index of norepinephrine activity.

Effects of exercise on blood pressure, plasma catecholamines, potassium and the electrocardiogram after diuretic and neural-blocking therapy for moderate hypertension.

Blood pressure control in mild and moderate hypertension may reduce morbidity and mortality. On the other hand, antihypertensive drugs may cause adverse metabolic, electrolyte, neural and hemodynamic alterations that detract from their effectiveness. The effect of hydrochlorothiazide (HCTZ) on some of these factors was compared with that of HCTZ and a sympatholytic drug in 20 hypertensive patients with left ventricular hypertrophy and retinopathy. HCTZ controlled blood pressure at rest and during maximum treadmill exercise (-12 mm Hg systolic and diastolic pressure (p less than 0.05), reduced left ventricular mass by 7% (p less than 0.05) and lessened aerobic impairment at maximum treadmill exercise by 45% (p less than 0.05). These effects were further improved after "neural blockade." A potential adverse effect of HCTZ--hypokalemia (-0.6 mEq/liter, p less than 0.01)--and the associated incidence of ectopy during effort (50%) were lessened after neutralizing neural tone. Combination therapy with low-dose diuretic and sympatholytic drugs was effective and well tolerated in patients with cardiac and vascular sequelae of moderately severe hypertension.

Efficacy of bucindolol in systemic hypertension.

The hemodynamic effects of oral bucindolol, a non-selective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilating properties, were studied at rest and during handgrip exercise with a flotation-directed pulmonary artery catheter in 12 patients with mild to moderate essential hypertension. After the initial dose of 150 mg of bucindolol, blood pressure (BP) was significantly reduced and cardiac output was increased (from 5.9 +/- 0.8 to 6.8 +/- 1.6 liters/min) in the supine position and during exercise (p less than 0.05). Systemic vascular resistance was reduced (from 1,555 +/- 339 to 1,311 +/- 467 dynes s cm-5, p less than 0.01) at rest and without significant changes during exercise. There were increases in heart rate (13 +/- 13%, p less than 0.01) and right atrial (69 +/- 77%, p less than 0.05), pulmonary arterial (38 +/- 24 %, p less than 0.001) and pulmonary artery wedge pressures (62 +/- 46%, p less than 0.001) during exercise. Bucindolol did not change these variables at rest or during exercise. Bucindolol increased plasma norepinephrine levels both at rest (from 330 +/- 151 to 588 +/- 320 ng/liter, p less than 0.01) and during exercise (from 468 +/- 220 to 685 +/- 390 ng/liter, p less than 0.05). After 4 weeks of bucindolol with doses of 50 to 200 mg 3 times daily, BP was reduced in both supine and standing positions (mean arterial BP of 11 +/- 7% [p less than 0.001] and 11 +/- 6% [p less than 0.001], respectively), without changes in cardiac output, systemic vascular resistance or plasma norepinephrine level.(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular mechanisms in the evolution of chronic myelocytic leukemia.

Chronic myelocytic or Ph1-positive acute lymphoblastic leukemias have been analyzed for alterations in a variety of proto-oncogenes and anti-oncogenes implicated in the progression of chronic myeloid leukemia (CML) from its chronic phase to blast crisis. The most frequent genetic change found in disease evolution is an alteration of the p53 gene involving a point mutation, a rearrangement or a deletion. These gene changes are common in myeloid and undifferentiated variants of blast crisis but are usually undetectable in lymphoid leukemic transformants. Other molecular changes also occur in the clonal evolution of CML. The retinoblastoma-susceptibility (Rb) gene is an anti-oncogene. Structural abnormalities of Rb are frequent in all types of human acute leukemia, but are particularly common in Ph1-positive leukemia of lymphoid phenotype including both Ph1-positive ALL and lymphoid blast crisis of CML. Changes in Rb occur early in the transition to blast crisis with loss of Rb protein being the common factor. Mutations in the N-RAS gene also occur, but are rare in typical blast crisis. They are sometimes seen in Ph1-negative myeloid blast crisis. Since changes in the p53 gene are generally associated with progression of disease of a myeloid phenotype and changes in the Rb gene occur more often with a lymphoid phenotype, a particular molecular alteration may influence the character of disease evolution in CML.

Primary hypertension: left ventricular mass and function, sympathetic nervous system activity, and therapy.

Left ventricular (LV) mass is a predictor of morbidity in patients with hypertension. To elucidate the mechanisms of left ventricular hypertrophy (LVH) in primary hypertension, we examined the relationships of LV mass, arterial blood pressure, and plasma norepinephrine--as a marker of sympathetic nervous system tone--in three populations of patients with mild or moderate hypertension. We found linking of neural tone with (a) arterial blood pressure in mild and moderate hypertension, (b) LV mass in moderate hypertension, and (c) diastolic function in mild hypertension, suggesting that neural tone is a factor in both the pathogenesis and the sequelae of hypertension. Additionally, elevated norepinephrine level may reflect subtle loss of diastolic function before hypertrophy is manifest. Both nondrug and drug therapy may regress LV mass after blood pressure reduction with disparate effects on neural tone.

A radioenzymatic assay for free and conjugated normetanephrine and octopamine excretion in man.

A radioenzymatic method for the measurement of free and conjugated normetanephrine (NMN) and octopamine (OCT) is described for human urine. The assay is based on the conversion of NMN or OCT to radiolabeled metanephrine (MN) or synephrine (SYN) by phenylethanolamine-N-methyl transferase (PNMT), using tritium-labeled S-adenosyl-methionine [3H]SAM as methyl donor. Thin-layer chromatographic separation yields an assay of high specificity. The sensitivity of the assay is 5 and 2.5 pg of NMN or OCT, respectively. The normal value of free and conjugated NMN was found to be 23 +/- 13 and 102 +/- 49 ng/mg creatinine. Four patients with pheochromocytoma had highly increased levels of free and conjugated NMN. The urinary excretions of free and total octopamine were 5.7 +/- 2.8 and 34.8 +/- 16.6 ng/mg of creatinine, respectively, in normal patients.

Neurohumoral mechanisms and left ventricular hypertrophy: effects of hygienic therapy.

To determine the effects of hygienic (non-drug) therapy on blood pressure (BP) control and its relationship to sympathetic tone and left ventricular mass (LVM) in primary hypertension, plasma norepinephrine (NE) and renin activity (PRA), LVM, and nutritional and behavioral status were assessed in 76 borderline to mild hypertensives. Pretherapy plasma NE was related to diastolic blood pressure (DBP) and PRA (r = 0.24, P less than .05 and r = 0.37, P less than .01, respectively). Plasma NE of high renin patients (221 +/- 52) (mean +/- SD) was greater than that of normal renin patients (159 +/- 61, ng/l, P less than .01). LVM was related to systolic blood pressure (SBP) (P less than .001), DBP (P less than .01) and urinary sodium (P less than .05), and inversely related to PRA (P less than .01). Septal wall thickness was related to hostility (r = 0.42, P less than .05). After seven weeks of hygienic therapy, DBP was reduced by 6 mmHg (P less than .01). The change in SBP was related to baseline plasma NE (P less than .05) and inversely related to LVM (P less than .05). These results suggest that raised sympathetic tone may be a pathogenic factor in primary hypertension and that hygienic therapy lowers BP more effectively in patients with raised sympathetic tone and low LVM.

Changes in plasma and cerebrospinal fluid electrolytes in hypercapnia.

A study on two groups of patients in acute respiratory failure with hypercapnia (18 subjects) and in hypercapnic coma (18 subjects) has been carried out to determine the related changes in sodium ion, potassium ion, chloride ion, urea and osmolality in blood and cerebrospinal fluid. There were significant differences between the two pathological states and particularly in coma, changes in transmembrane active transport of electrolytes are significantly related to high concentrations of CO2 in the brain.

[Experimental research on the effect of electro-acupuncture on reparative processes]. / Ricerche sperimentali sull'azione dell'elettroagopuntura nei processi riparativi.

With a view to clarifying the mechanism whereby electroacupuncture aids teh repair of trophic ulcers, including inveterate forms resistant to ordinary treatments, reference is made to histochemical findings and histological findings in periulcerous tissues and experimental research into wound healing. Preliminary work showed that electroacupuncture improves the blood supply to ulcerous tissue and the local biochemistry, and accelerates the repair process. Experimental work also made it clear that the method, when use on alternate days with the modalities employed in clinical practice, accelerates the healing of wounds in the experimental animal.