Cervical cancer screening with HPV testing in the Valcamonica (Italy) screening programme.

OBJECTIVE: We present the results of the first screening round and the first year of the second round of the Valcamonica Human Papillomavirus (HPV) pilot screening project. SETTING: From 2010 to 2012, the entire target female population (aged 25-64) was invited to the first HPV screening round in an area where Pap test screening had been active since 2002. METHODS: For HPV-negative women, the interval was three years. For HPV-positive women, a cytological smear was stained and interpreted. Positive cytologies were referred to colposcopy; negatives were referred to repeat HPV after one year. If HPV was persistently positive, women were referred to colposcopy; if negative, to normal screening. RESULTS: In 2010-12 18728 women were screened, slightly higher participation than with Pap test (18233 64.7%); 1633 were HPV-positive (8.7%); 843 were positive at cytology triage (referral rate at baseline 4.5%). Of those referred at the one year HPV test, 84% complied (660/780); 356 were persistently positive (1.9%). The total referral rate was 6.4% compared with 3.7% for the Pap test. The detection rate was 9.2/1000 compared with 5.0% for the Pap test. The HPV positivity rate during the second round in women previously negative was 3.9% and the detection rate in HPV-positive cytology-positive women was 0.8/1000. CONCLUSIONS: HPV-based screening increases colposcopies at the first round, but also strongly increases the detection rate. At the second round, HPV prevalence was much lower and the detection rate also fell, corroborating the need for longer screening intervals in HPV-negative women.

Optical transmission through double-layer, laterally shifted metallic subwavelength hole arrays.

We measure the transmission of IR radiation through double-layer metal films with periodic arrays of subwavelength holes. When the two metal films are placed in sufficiently close proximity, two types of transmission resonances emerge. For the surface plasmon mode, the electromagnetic field is concentrated on the outer surface of the entire metallic layer stack. In contrast, for the guided mode, the field is confined to the gap between the two metal layers. Our measurements indicate that, as the two layers are laterally shifted from perfect alignment, the peak transmission frequency of the guided mode decreases significantly, while that of the surface plasmon mode remains largely unchanged, in agreement with numerical calculations.

Nanopores in solid-state membranes engineered for single molecule detection.

A nanopore is an analytical tool with single molecule sensitivity. For detection, a nanopore relies on the electrical signal that develops when a molecule translocates through it. However, the detection sensitivity can be adversely affected by noise and the frequency response. Here, we report measurements of the frequency and noise performance of nanopores

Casimir force on a surface with shallow nanoscale corrugations: geometry and finite conductivity effects.

We measure the Casimir force between a gold sphere and a silicon plate with nanoscale, rectangular corrugations with a depth comparable to the separation between the surfaces. In the proximity force approximation (PFA), both the top and bottom surfaces of the corrugations contribute to the force, leading to a distance dependence that is distinct from a flat surface. The measured Casimir force is found to deviate from the PFA by up to 10%, in good agreement with calculations based on scattering theory that includes both geometry effects and the optical properties of the material.

Measurement of the Casimir force between a gold sphere and a silicon surface with nanoscale trench arrays.

We report measurements of the Casimir force between a gold sphere and a silicon surface with an array of nanoscale, rectangular corrugations using a micromechanical torsional oscillator. At distances between 150 and 500 nm, the measured force shows significant deviations from the pairwise additive formulism, demonstrating the strong dependence of the Casimir force on the shape of the interacting bodies. The observed deviation, however, is smaller than the calculated values for perfectly conducting surfaces, possibly due to the interplay between finite conductivity and geometry effects.

Controlling the phase delay of light transmitted through double-layer metallic subwavelength slit arrays.

We demonstrate that the phase of light transmitted through double-layer subwavelength metallic slit arrays can be controlled through lateral shift of the two layers. Our samples consist of two aluminum layers, each of which contains an array of subwavelength slits. The two layers are placed in sufficient proximity to allow coupling of the evanescent fields at resonance. By changing the lateral shift between the layers from zero to half the period, the phase of the transmitted electromagnetic field is increased by pi, while the transmitted intensity remains high. Such a controllable phase delay could open new capabilities for nanophotonic devices that cannot be achieved with single-layer structures.

Small-Signal Performance and Modeling of sub-50nm nMOSFETs with f above 460-GHz.

We have fabricated and tested the performance of sub-50nm gate nMOSFETs to assess their suitability for mixed signal applications in the super high frequency (SHF) band, i.e. 3-30GHz. For a 30nm×40 µm×2 device, we found f(T) =465GHz at V(ds)=2V, V(g)=0.67V, which is the highest cut-off frequency reported for a MOSFET produced on bulk silicon substrate so far. However, our measurements of f(max) and noise figure indicate that parasitics impose limitations on SHF operation. We also present a high-frequency ac model appropriate to sub-50nm gate length nanotransistors, which incorporates the effects of the parasitics. The model accurately accounts for measurements of the S and Y parameters in the frequency range from 1 to 50GHz.

Chemical modification of the electronic conducting states in polymer nanodevices.

Organic materials offer new electronic functionality not available in inorganic devices. However, the integration of organic compounds within nanoscale electronic circuitry poses new challenges for materials physics and chemistry. Typically, the electronic states in organic materials are energetically misaligned with the Fermi level of metal contacts. Here, we study the voltage-induced change in conductivity in nanoscale devices comprising a monolayer of polyelectrolyte macromolecules. The devices are fabricated using integrated shadow masks. Reversible switching is observed between conducting (ON) and non-conducting (OFF) states in the devices. The open design of our devices easily permits chemical modification of the polyelectrolyte, which we show has a pronounced effect on the ON-OFF switching. We suggest that the switching voltage ionizes the polymers, creating a conducting channel of electronic levels aligned with the contact Fermi level.

Optical transmission through double-layer metallic subwavelength slit arrays.

We present measurements of transmission of infrared radiation through double-layer metallic grating structures. Each metal layer contains an array of subwavelength slits and supports transmission resonance in the absence of the other layer. The two metal layers are fabricated in close proximity to allow coupling of the evanescent field on individual layers. The transmission of the double layer is found to be surprisingly large at particular wavelengths, even when no direct line of sight exists through the structure as a result of the lateral shifts between the two layers. We perform numerical simulations using rigorous coupled wave analysis to explain the strong dependence of the peak transmission on the lateral shift between the metal layers.

Kinetics of the development and recovery of the lung from IgE-mediated inflammation: dissociation of pulmonary eosinophilia, lung injury, and eosinophil-active cytokines.

Events occurring up to 16 d after antigen challenge were characterized using a novel protocol employing four bronchoscopies, two segmental antigen challenge (SAC) procedures (on Days 1 and 2), and six bronchoalveolar lavages (BALs) (on Days 1, 2, 9, and 16) in three groups: ragweed allergic asthmatics with dual phase airway reactions (AA-D), allergic asthmatics with a single early airway reaction (AA-S), and nonallergic nonasthmatic control subjects. In AA-D subjects, SAC produced a marked eosinophilic inflammatory response at 24 h associated with eosinophil degranulation (eosinophil cationic protein [ECP] in BAL fluid) and lung injury, which largely resolved by Day 16. When the second antigen-challenged segment (SAC performed on Day 2) was lavaged 7 d after challenge (Day 9), a persistent pulmonary eosinophilia was noted accompanied by minimal elevations in ECP and albumin. Eosinophil-active cytokines showed unique patterns: interleukin-5 (IL-5) increased in the antigen segment on Day 2 then returned to baseline after 7 d; granulocyte-macrophage colony-stimulating factor (GM-CSF) peaked at Day 2 but was persistently elevated throughout Day 16 in antigen segments, and increased in control segments at late time points; IL-3 levels were constant and similar in antigen and control segments. Changes were specific to AA-D subjects in comparison with control subjects. Elements of the IgE-mediated pulmonary inflammatory response differ markedly in their development and resolution.

Neutrophil recruitment as a factor limiting injury or promoting recovery from acute lung injury.

We studied 1) neutrophil mobilization in sheep given endotoxin (10 ng.kg-1.min-1, n = 5) for 4 h, 2) surviving (n = 17) and nonsurviving sheep (n = 8) during a 12-h infusion of endotoxin, and 3) adult sheep (n = 8) or lambs (n = 8) infused with endotoxin for 12 h. Bone marrow cells of sheep declined from a baseline value of 10,533 +/- 1,784 to 5,966 +/- 1,980 cells/microliter (P < 0.05) 4 h after endotoxin. After 12 h of endotoxin infusion, circulating neutrophils remained reduced from baseline values of 2,000-4,000 cells/microliter to 343 +/- 70 in lambs and 484 +/- 236 in nonsurviving sheep, while beginning to recover in surviving sheep to 1,838 +/- 467 cells/microliter. In lambs and nonsurviving sheep, a 12-h infusion of endotoxin increased lung lymph protein clearance tenfold compared with a fivefold increase in surviving sheep. Neutrophils cultured from sheep bone marrow exposed to lamb postendotoxin plasma failed to increase in cell number (609 +/- 229 to 610 +/- 182 cells/microliter), whereas similar cells exposed to adult sheep postendotoxic plasma showed a significant increase in cell number (1,069 +/- 101 to 2,293 +/- 448 cells/microliter, P < 0.05). Our results are consistent with the hypothesis that the ability to recruit neutrophils to the circulation during periods of inflammation is important in limiting the severity of acute lung injury.

Beta 2-agonist-elevated stress response in human bronchial epithelial cells in vivo and in vitro.

Recent studies report high baseline levels of stress (heat shock) proteins in bronchial epithelial cells from asthmatic individuals. The promoter of the gene encoding the 72-kDa heat shock protein has an element responsive to cAMP, which may be affected by beta-agonists. This study examined stress protein levels in subjects enrolled in a segmental lung allergen challenge study to determine whether beta-agonist medication could contribute to a stress response. Subjects were divided on the basis of no premedication (n = 17), metered dose inhalations of albuterol (n = 24), or placebo inhalation (n = 3) prior to bronchoscopy. Levels of the inducible stress protein Hsp72 and constitutive Hsp73 were quantitated in bronchial epithelial cells from brush biopsy of allergic nonasthmatic, allergic asthmatic, and normal individuals. Mean levels were increased significantly (p < 0.003 and p < 0.004, respectively) in those subjects who received albuterol premedication. No significant differences were found between clinical groups of individuals or for placebo inhalation vs nonpremedication. Albuterol in vitro increased the levels of Hsp72 and Hsp73 in epithelial cells from either nonpremedicated or placebo-treated donors; the Hsp72 levels correlated linearly with increased albuterol concentration (r = 0.81, p < 0.01). Therefore, beta-agonists elevate or prolong an elevated stress response in epithelial cells, possibly through cAMP-mediated effects.

Famciclovir: review of clinical efficacy and safety.

Famciclovir is the well-absorbed oral form of penciclovir, an antiviral agent with potent activity against varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) and 2 (HSV-2). After oral administration, famciclovir is rapidly converted to penciclovir with a bioavailability of 77%. penciclovir is efficiently phosphorylated to the active metabolite, penciclovir-triphosphate, and has a prolonged intracellular half-life of approximately 9-10 h in VZV-infected cells, and 10 and 20 h in cells infected with HSV-1 and HSV-2, respectively. Two multicenter clinical trials have shown that famciclovir given during the acute zoster phase accelerated healing of cutaneous lesions. More importantly, in a placebo-controlled study, famciclovir reduced the duration of postherpetic neuralgia (PHN), particularly in elderly patients. Famciclovir has also been proven effective in treating recurrent genital herpes, as demonstrated by a reduction in times to cessation of viral shedding, complete healing, and loss of all symptoms. One study showed that suppressive therapy with famciclovir was effective in reducing genital herpes episodes in patients with frequent recurrences. A promising new area of investigation for famciclovir is controlling virus replication in patients with chronic hepatitis B virus (HBV) or HBV reinfections after liver transplant. Results from a double-blind, placebo-controlled, pilot study and several case reports have shown that famciclovir, alone or in combination with other agents, decreased HBV-DNA levels and was tolerated with long-term treatment. Available clinical data indicate that famciclovir is an effective agent for treating herpes and holds significant promise for the treatment of chronic HBV infection HBV reinfection after liver transplantation.

Antiviral therapy of acute herpes zoster in older patients.

Although herpes zoster (shingles) can occur in anyone with a history of chickenpox, it is more prevalent and usually more severe in older patients (i.e. persons over 50 years of age). While the cutaneous manifestations of shingles usually resolve in approximately 4 weeks, the pain can persist for several months, or even years in the untreated patient. This pain following healing of the skin, termed post-herpetic neuralgia (PHN), can be very severe. Three well tolerated and effective antiviral drugs are available for the therapy of acute herpes zoster. The nucleoside analogues, aciclovir, famciclovir and valaciclovir, appear to shorten the duration of PHN to a similar degree, but none affects the incidence of PHN. Aciclovir is taken 5 times daily for 7 days, while famciclovir is taken 3 times daily for 7 days. Valaciclovir, the L-valyl ester of aciclovir, when taken orally, produces plasma levels of aciclovir equivalent to those seen following intravenous administration of aciclovir. Valaciclovir has not only been proved to be more efficient than aciclovir (i.e. 3 times daily administration) but also more effective than aciclovir in shortening the duration of PHN. Current studies are determining the relative efficacy of valaciclovir versus famciclovir. Presently, a fourth drug, sorivudine, is being compared with aciclovir for the therapy of acute herpes zoster in older patients, but data from these trials are not yet available. Corticosteroids have been used to treat herpes zoster for much longer than the antiviral drugs, but the effect of corticosteroids on PHN does not appear to be consistent. Corticosteroids plus aciclovir did not provide an added benefit over aciclovir alone in one study but this combination did appear to improve the quality of life of older patients in another investigation. The recent availability of the varicella zoster vaccine may cause shingles to be an uncommon and/or mild disease by the mid twenty-first century. Meanwhile, the search continues for more effective and efficient therapies for acute herpes zoster with the primary goal in older patients to affect the most important sequela of zoster in this population, PHN.

Cutaneous manifestations of HIV-1 infection.

Infection with the human immunodeficiency virus (HIV) leads to a chronic disarmament of the immune system. The process is progressive, having different manifestations as the status of the immune system slowly deteriorates. Some of the most common manifestations of HIV infection are cutaneous in origin, and they can have infectious, neoplastic, or noninfectious or non-neoplastic etiologies. A brief history of HIV is given, and the most common cutaneous presentations of the virus infection of interest to podiatrists are outlined.

Development of human papillomavirus type 16 associated squamous cell carcinoma of the scrotum in a patient with Darier's disease treated with systemic isotretinoin.

In contrast to squamous cell carcinoma of the penis, scrotal carcinoma has historically been associated with exposure to environmental or industrial carcinogens and has only rarely been correlated with human papillomavirus. We report on a patient with squamous cell carcinoma of the scrotum in which human papillomavirus type 16 was integrated into the tumor cell genome, suggesting a causal role of human papillomavirus in the development of squamous cell carcinoma of the scrotum. Other unique features of our case include the presence of Darier's disease, an uncommon genodermatosis, and treatment with oral retinoids, which have prophylactic value in the prevention of cutaneous malignancies.

Endotoxin infusion in anesthetized sheep is associated with intrapulmonary sequestration of leukocytes that immunohistochemically express tumor necrosis factor-alpha.

Plasma levels of tumor necrosis factor-alpha (TNF-alpha) peak between 2 and 4 h during a 12-h continuous infusion of endotoxin in awake sheep. We hypothesized that a source of this TNF-alpha is the pool of leukocytes that accumulate in the pulmonary circulation. To test this hypothesis, we physiologically monitored six anesthetized sheep during baseline and 4-h endotoxin infusion periods (10 ng/kg x min). We obtained open-lung biopsies at baseline and at 20 min and 2 and 4 h during the endotoxin infusion period for immunohistochemical localization of TNF-alpha. The plasma concentration of TNF-alpha increased from an average baseline concentration of 0.06 +/- 0.03 ng/ml (mean +/- SD) to a peak of 1.40 +/- 0.28 ng/ml at 2 h of the endotoxin infusion. We observed increased cytoplasmic TNF-alpha immunoreactivity in situ among neutrophils and intravascular mononuclear phagocytes during the endotoxin infusion compared with baseline. Also, the number of immunopositive leukocytes increased in the pulmonary circulation during the continuous infusion of endotoxin. We conclude that TNF-alpha-producing leukocytes accumulate in the pulmonary circulation during endotoxemia. These cells probably contribute to both the rise in the circulating levels of TNF-alpha and the development of acute lung injury.

sVCAM-1 levels after segmental antigen challenge correlate with eosinophil influx, IL-4 and IL-5 production, and the late phase response.

Evidence from in vitro studies suggests a potential role for vascular cell adhesion molecule-1 (VCAM-1) in eosinophil trafficking. We hypothesized that induction of VCAM-1 occurs in the lung during IgE-mediated airway inflammation in humans. The technique of segmental antigen provocation followed by bronchoalveolar lavage (BAL) at 24 h was used to study 27 ragweed-allergic asthmatics (AA) and 18 atopic nonasthmatics (ANA). Total and differential cell counts were performed, and IL-4, IL-5, and soluble (VCAM) (sVCAM) levels in concentrated BAL fluid were measured by ELISA. A large increase in sVCAM levels after segmental challenge in both AA and ANA (1.79 +/- 0.31 to 139.39 +/- 68.58 ng/ml, p < 0.0005 and 2.85 +/- 0.80 to 98.25 +/- 77.35 ng/ml, p < 0.05, respectively) was observed. BAL IL-4 and IL-5 also increased after challenge (IL-4: 51.7 +/- 17.72 to 150.1 +/- 58.82 pg/ml, 0.05 < p < 0.10, n = 20 for AA, and 36.6 +/- 9.05 to 116.8 +/- 51.5 pg/ml, 0.05 < p < 0.10, n = 15 for ANA; IL-5: 0 to 2.67 +/- 1.62 ng/ml, p < 0.01, n = 16 for AA, and 0 to 2.87 +/- 2.16 ng/ml, 0.05 < p < 0.10, n = 10 for ANA). In both groups, the majority of the increase in sVCAM, IL-4, and IL-5 was accounted for by subjects who displayed a dual phase response after whole-lung antigen inhalation. This fact, plus the strong correlation observed between postchallenge sVCAM, IL-4, and IL-5 levels and eosinophil influx, suggests that VCAM, IL-4, and IL-5 play important roles in the recruitment of eosinophils to the lung of humans after antigen challenge.

Interferons in human papillomavirus infections.

Human papillomavirus (HPV) infections usually present as benign warts (e.g., condyloma acuminatum, CA) but can also be responsible for dysplasia and carcinoma. Therapeutic options include chemotherapeutic agents, cryotherapy and surgery, but all these treatments are anti-tumor, not anti-viral. Interferons (IFNs) are the only anti-viral drugs approved for the therapy of benign HPV-related lesions. While IFN-alpha, IFN-beta and IFN-gamma have all been tested against CA, most information is available on IFN-alpha which appears efficacious via a number of routes of administration, schedules and dosages with an acceptable safety profile. The highest rate of success with IFN-alpha therapy, in terms of reduced recurrence rates of CA was reported from studies in which all visible lesions were surgically removed with subsequent administration of subcutaneous local IFN-alpha. Less data is available on the efficacy of IFNs in the treatment of HPV-related dysplasia and carcinoma, but combination therapy (e.g., IFN-alpha plus retinoids for cervical carcinoma) appears promising. Future advances in control of HPV-related lesions are expected to continue to involve IFN combined with non-antiviral therapies as well as the use of exogenous inducers of IFNs and other cytokines.

In vitro release of salicylic acid from lanolin alcohols-ethylcellulose films.

Lanolin alcohols-ethylcellulose films were investigated as a potential drug delivery system for the controlled release of salicylic acid. The effects of changes in film composition, drug concentration, drug solubility, and stirrer speed on the in vitro release of salicylic acid have been examined. The drug release has been found to obey a diffusion-controlled matrix model and square root of time release profile both in the suspension and solution cases.