Bioadhesive film for dermal and transdermal drug delivery

This paper describes an innovative transdermal drug delivery system, a monolaminated bioadhesive film in which the usual constituents of transdermal patches (backing, drug and adhesive) have been condensed in one single layer, denominated Patch-non-Patch. The main characteristics of the film is that it is not self-adhesive in the dry state but becomes adhesive only when applied on wet skin. This characteristic is due to the presence of a small amount of adhesive, unable to make the system self-adhesive, but capable of restoring the adhesiveness in contact with a small amount of water. From the results obtained to date, it appears that the technology Patch-non-Patch has the potentiality to be successfully applied to the pharmaceutical and cosmetic market. On the skin the film is flexible, invisible and adapts to all skin irregularities. The system has been shown to be highly efficient, releasing a high percentage of the active included in most cases. Additionally, the inclusion of other excipients can modulate drug delivery, thus improving the versatility of the product. Finally, the second generation Patch-non-Patch, made occlusive on the skin surface, can further broaden the potential application.     

Optomechanical response of human and monkey lenses in a lens stretcher

PURPOSE: To quantify the forces necessary to change the shape and optical power of human and monkey lenses. METHODS: Cynomolgus monkey (n = 48; age: 3.8-11 years), rhesus monkey (n = 35; age: 0.7-17 years) and human (n = 20, age 8-70 years) eyes obtained postmortem, including the lens, capsule, zonules, ciliary body, and sclera were mounted in an optomechanical lens-stretching system. Starting at zero load, the lenses were symmetrically stretched in a stepwise fashion in 0.25- or 0.5-mm steps. The load, lens diameter, inner ciliary body diameter, and lens power were measured at each step and the diameter- and power-load responses were quantified. RESULTS: The diameter- and power-load responses were found to be linear in the physiologically relevant range of stretching. The average change in cynomolgus, rhesus, and human lens diameter, respectively, was 0.094, 0.109, and 0.069 mm/g in young lenses, and 0.069, 0.067, and 0.036, mm/g in older lenses. For the same lenses, the average change in lens power was -3.73, -2.83, and -1.22 D/g in young lenses and -2.46, -2.16, and -0.49 D/g in older lenses. CONCLUSIONS: The force necessary to change the lens diameter and lens power increases with age in human and monkey lenses. The results agree with the Helmholtz theory of accommodation and with presbyopia theories that predict that the force required to disaccommodate the lens increases with age.     

Rupture of Internal Iliac Artery Aneurysm into the Bladder following Aortic Aneurysm Repair

This report describes a case of ruptured internal iliac artery aneurysm into the bladder after repair of an infrarenal abdominal aortic aneurysm. Aortic repair consisted of resection of the aneurysm followed by prosthetic interposition to reestablish arterial continuity. During the postoperative period, the patient had ischemia of left colon, which was successfully treated by the Hartmann procedure. A right internal iliac artery aneurysm measuring 50 mm in diameter was demonstrated by an abdominal CT scan during the initial hospitalization but was considered stable, since ultrasonography showed no change in diameter at 3 months and 1 year. The patient was lost from follow-up until 3 years later when he was hospitalized after rupture of the right iliac artery aneurysm, then measuring 120 mm in diameter, into the bladder. Surgical repair was undertaken. The procedure involved aortobifemoral bypass with suture of the bladder defect and branches of the internal iliac artery by the endoaneurysmal route. Postoperative recovery was uneventful. Upon reexamination 1 month after discharge from the hospital, the patient was asymptomatic. This rare case confirms the gravity of internal iliac artery aneurysm and the importance of therapeutic management to prevent rupture.     

Differential production in vitro of antigen specific IgG1, IgG3 and IgA: a study in Schistosoma haematobium infected individuals

This study has evaluated the individual control of isotype production and the influence of external signals that can be experimentally provided in vitro, in antibody responses to two different recombinant Schistosoma antigens (Sh28GST and TPx-1). Peripheral blood mononuclear cells or enriched B cell fractions obtained from S. haematobium infected Senegalese adults were induced to terminal differentiation in vitro. The production of antibody to either antigen was donor-dependent and for each donor it was antigen-dependent. Differentiation to IgG1 and IgG3 production, and possibly IgA, specific to these conserved parasite antigens could be regulated differentially in vitro. Exogenous IL-2 and IL-10 or IL-10 and TGF-beta led to the production of specific IgG3 or IgG1 and/or IgA, respectively. This is the first report on such experimentally induced differential regulation of antigen-specific IgG1 and IgG3. This may have implications in designing protocols for protein based-vaccinations aiming at eliciting antibody responses of certain protective-type isotypes.     

Increased mortality in HIV/HCV-coinfected compared to HCV-monoinfected patients in the DAA era due to non-liver-related death

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Vascular stenting for palliation of superior vena cava obstruction in non-small-cell lung cancer patients: a future 'standard' procedure?

BACKGROUND: Stenting is a relatively new option in the management of superior vena cava obstruction (SVCO), but available data often concern non-malignant and/or various malignant diseases. OBJECTIVE: The aim of this study was to assess the efficacy of vascular stenting as a first-choice treatment in SVCO in the exclusive setting of NSCLC. PATIENTS AND METHODS: Retrospective study of NSCLC patients with SVCO treated in the past year. Demographic data, disease characteristics, etiologic and palliative treatment (use of vascular stenting) were recorded as well as treatment outcome and survival. RESULTS: 17 patients were recruited. Eight had vascular stenting while 9 did not. Except for stenting, there was no difference between the two groups (median age 54 years; 80% men; 53% stage IIIB and 47% stage IV). Stenting (median length 60 mm) achieved complete resolution of SVCO more frequently (75 vs. 25%, p = 0.05) and faster (2 vs. 21 days, p = 0.002) without immediate or delayed complication. All patients with stents received anticoagulation therapy. Relapse rate after complete response (33 g, 50%, p = 0.6) was lower and time to relapse (6.5 g, 2 months) was longer for patients undergoing stenting, without reaching statistical significance. Median overall survival was not statistically different (8 and 5 months, p = 0.06). CONCLUSIONS: This study demonstrated the effectiveness of vascular stenting for SVCO in NSCLC patients. The high response rate, quick effect and safety of vascular stenting make this palliative treatment a candidate as a potential standard procedure. The results, however, must be confirmed in a prospective randomized trial including quality of life assessment.     

Prognostic significance of mediastinal <Superscript>18</Superscript>F-FDG uptake in PET/CT in advanced ovarian cancer

Purpose  

To evaluate the prognostic significance of increased mediastinal ¹⁸F-FDG uptake in PET/CT for the staging of advanced ovarian cancer.     

Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors

Purpose

[¹⁸F]SP203 (3-fluoro-5-(2-(2-([¹⁸F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived ¹¹C (t _1/2?=?20.4?min) and to characterize its behavior as a radioligand with PET in the monkey.

Methods

Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [¹¹C]cyanide ion rapidly gave [¹¹C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [¹¹C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [¹¹C]SP203 in human blood in vitro was also measured.

Results

The iodo precursor gave [¹¹C]SP203 in higher radiochemical yield (>98?%) than the bromo precursor (20–52?%). After intravenous administration of [¹¹C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5?min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [¹¹C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [¹¹C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites. By contrast, [¹¹C]SP203 was stable in human blood in vitro.

Conclusion

[¹¹C]SP203 emulates [¹⁸F]SP203 with regard to providing a sizeable mGluR5-specific signal in monkey brain, and advantageously avoids troublesome accumulation of radioactivity in bone. Although [¹¹C]SP203 is unsuitable for mGluR5 quantification in monkey brain, its evaluation as a PET radioligand for studying human brain mGluR5 is nevertheless warranted.     

Characterization of pandemic influenza immune memory signature after vaccination or infection

The magnitude, quality, and maintenance of immunological memory after infection or vaccination must be considered for future design of effective influenza vaccines. In 2009, the influenza pandemic produced disease that ranged from mild to severe, even fatal, illness in infected healthy adults and led to vaccination of a portion of the population with the adjuvanted, inactivated influenza A(H1N1)pdm09 vaccine. Here, we have proposed a multiparameter quantitative and qualitative approach to comparing adaptive immune memory to influenza 1 year after mild or severe infection or vaccination. One year after antigen encounter, severely ill subjects maintained high levels of humoral and polyfunctional effector/memory CD4⁺ T cells responses, while mildly ill and vaccinated subjects retained strong cellular immunity, as indicated by high levels of mucosal homing and degranulation markers on IFN-γ⁺ antigen-specific T cells. A principal component analysis distinguished 3 distinct clusters of individuals. The first group comprised vaccinated and mildly ill subjects, while clusters 2 and 3 included mainly infected individuals. Each cluster had immune memory profiles that differed in magnitude and quality. These data provide evidence that there are substantial similarities between the antiinfluenza response that mildly ill and vaccinated individuals develop and that this immune memory signature is different from that seen in severely ill individuals.