Isotype selection for antibody-based cancer therapy.

The clinical application of monoclonal antibodies (mAbs) has revolutionized the field of cancer therapy, as it has enabled the successful treatment of previously untreatable types of cancer. Different mechanisms play a role in the anti-tumour effect of mAbs. These include blocking of tumour-specific growth factor receptors or of immune modulatory molecules as well as complement and cell-mediated tumour cell lysis. Thus, for many mAbs, Fc-mediated effector functions critically contribute to the efficacy of treatment. As immunoglobulin (Ig) isotypes differ in their ability to bind to Fc receptors on immune cells as well as in their ability to activate complement, they differ in the immune responses they activate. Therefore, the choice of antibody isotype for therapeutic mAbs is dictated by its intended mechanism of action. Considering that clinical efficacy of many mAbs is currently achieved only in subsets of patients, optimal isotype selection and Fc optimization during antibody development may represent an important step towards improved patient outcome. Here, we discuss the current knowledge of the therapeutic effector functions of different isotypes and Fc-engineering strategies to improve mAbs application.

Analytical expression for Risken-Nummedal-Graham-Haken instability threshold in quantum cascade lasers.

We have obtained a closed-form expression for the threshold of Risken-Nummedal-Graham-Haken (RNGH) multimode instability in a Fabry-Pérot (FP) cavity quantum cascade laser (QCL). This simple analytical expression is a versatile tool that can easily be applied in practical situations which require analysis of QCL dynamic behavior and estimation of its RNGH multimode instability threshold. Our model for a FP cavity laser accounts for the carrier coherence grating and carrier population grating as well as their relaxation due to carrier diffusion. In the model, the RNGH instability threshold is analyzed using a second-order bi-orthogonal perturbation theory and we confirm our analytical solution by a comparison with the numerical simulations. In particular, the model predicts a low RNGH instability threshold in QCLs. This agrees very well with experimental data available in the literature.

'On-demand' romiplostim therapy in immune thrombocytopenia.

WHAT IS KNOWN AND OBJECTIVE: Although thrombopoietin receptor agonists are a second-line treatment for refractory immune thrombocytopenia (ITP), we lack guidelines recommending maintenance modality in patients who achieve complete remission (CR). CASE SUMMARY: We report a patient with refractory ITP who achieved CR on romiplostim. Obtaining romiplostim for 6 months of therapy, we decided to try extending this by modifying the standard treatment regimen. Romiplostim was successfully administered 'on-demand', only if the patient's platelet count dropped below 150 × 109 /L, over a period of 12 months. WHAT IS NEW AND CONCLUSION: The strategy of 'on-demand' therapy is a promising procedure for the maintenance of response, lowering costs and improving treatment safety.

Tunable continuous wave emission via phase-matched second harmonic generation in a ZnSe microcylindrical resonator.

Whispering gallery mode microresonators made from crystalline materials are of great interest for studies of low threshold nonlinear phenomena. Compared to amorphous materials, crystalline structures often exhibit desirable properties such as high indices of refraction, high nonlinearities, and large windows of transparency, making them ideal for use in frequency comb generation, microlasing and all-optical processing. In particular, crystalline materials can also possess a non-centrosymmetric structure which gives rise to the second order nonlinearity, necessary for three photon processes such as frequency doubling and parametric down-conversion. Here we report a novel route to fabricating crystalline zinc selenide microcylindrical resonators from our semiconductor fibre platform and demonstrate their use for tunable, low power continuous wave second harmonic generation. Visible red light is observed when pumped with a telecommunications band source by a process that is phase-matched between different higher order radial modes, possible due to the good spatial overlap between the pump and signal in the small volume resonator. By exploiting the geometrical flexibility offered by the fibre platform together with the ultra-wide 500-22000 nm transmission window of the ZnSe material, we expect these resonators to find use in applications ranging from spectroscopy to quantum information systems.

Ultrafast optical control using the Kerr nonlinearity in hydrogenated amorphous silicon microcylindrical resonators.

Microresonators are ideal systems for probing nonlinear phenomena at low thresholds due to their small mode volumes and high quality (Q) factors. As such, they have found use both for fundamental studies of light-matter interactions as well as for applications in areas ranging from telecommunications to medicine. In particular, semiconductor-based resonators with large Kerr nonlinearities have great potential for high speed, low power all-optical processing. Here we present experiments to characterize the size of the Kerr induced resonance wavelength shifting in a hydrogenated amorphous silicon resonator and demonstrate its potential for ultrafast all-optical modulation and switching. Large wavelength shifts are observed for low pump powers due to the high nonlinearity of the amorphous silicon material and the strong mode confinement in the microcylindrical resonator. The threshold energy for switching is less than a picojoule, representing a significant step towards advantageous low power silicon-based photonic technologies.

Thalassemia major. A report of two cases with severe skeletal involvement.

Beta thalassemia major is rare in Serbia. Previously incurable, affected patients now live to adulthood with regular blood transfusions. The improvement in supportive treatment over recent decades has given rise to many more patients suffering from the associated metabolic complications of anaemia and iron overload, such as osteopenia and other skeletal changes. We present two patients with severe beta thalassemia major from early childhood, who encountered pathological long-bone fractures during the clinical course of their disease. One suffered a distal femoral diaphyseal fracture, and the second a distal tibia fracture. Both fractures occurred in osteopenic bone and were managed non-operatively due to the patients' general medical condition. Despite intense medical intervention, both patients died from disease progression within one year of their fractures, aged 23 and 24 years. As life expectancy rises it is anticipated that an increased number of beta thalassemia major patients will suffer pathological long-bone and other osteoporotic fractures. These fractures appear to both herald and contribute to a general clinical deterioration of this disease. Advances in stem-cell technology may hold the key for a definitive cure.

Ventricular and vascular remodelling effects of the angiotensin II receptor blocker telmisartan and/or the angiotensin-converting enzyme inhibitor ramipril in hypertensive patients.

Angiotensin II induces inflammatory activation of vascular smooth muscle cells and can cause left ventricular hypertrophy (LVH). Telmisartan is an angiotensin II receptor blocker with demonstrated beneficial effects on cardiac and vascular structure and function in animal models. The angiotensin-converting enzyme inhibitor ramipril also reduces ventricular and vascular remodelling. The open-label study observed 75 treatment-naive, moderately or severely hypertensive (systolic blood pressure 160-190 mmHg, diastolic blood pressure 90-110 mmHg) patients (age range, 42-58 years) treated with once-daily telmisartan 40 mg force-titrated to 80 mg after 1 month (n=25), once-daily ramipril 2.5 mg force-titrated to 5 mg after 1 month (n=25), or once-daily telmisartan 40 mg plus ramipril 2.5 mg (n=25); the total duration of treatment was 6 months. At baseline, blood pressure, left ventricular mass index (LVMI), carotid intima-media thickness (IMT) and carotid cross-sectional intima-media area (CSA) were measured. Measurements were repeated 1, 3 and 6 months after initiation of treatment. After 6 months, comparable blood pressure reductions were achieved with the three treatments. Reductions in LVMI after 6 months' treatment were 11.4%, 9.9% and 15.6% with telmisartan, ramipril, and telmisartan plus ramipril, respectively. Respective reductions in IMT were 14.6%, 12.0% and 18.2%, and for CSA were 7.8%, 4.3% and 11.5%. In conclusion, treatment with telmisartan or ramipril for 6 months resulted in regression of LVH and vascular remodelling. When a combination of telmisartan and ramipril was administered, additional regression and remodelling occurred.

[Health care delivery in the period of crises by means of EPI design methodology]. / Koriscenje zdravstvene sluzbe u uslovima krize primenom metoda brze procene.

New methods "Rapid health assessment" fulfill the request for a methodologically clear and efficient way of gaining the recent data, using relatively limited resources. The aim of the study was an assessment of health care delivery and problems in its realization and the population health status, in the period of crises (and of 1993/begining of 1994). The study showed that first effects of crises are shown in the field of health care delivery and than in the population health status. The difficulties were not the same for all, children and urgent cases had less problems than others. The morbidity structure among children and adults was changed. The morbidity structure among children and adults was changed in comparison with routine statistical data. The period of crises has been too short to draw any definitive conclusions.

Microbial contamination of harvested bone marrow and peripheral blood.

The incidence and clinical consequences of microbiological contamination of autologous bone marrow and peripheral blood progenitor cells are not well documented. We therefore retrospectively analysed our experience with bacterial or fungal contamination of harvested bone marrow and/or peripheral blood. From January 1987 to the end of January 1994, 499 patients were harvested or which 301 were transplanted. A total of 3910 specimens obtained during three stages in the processing were assessed for microbial contamination: (1) in the operating room immediately after harvesting (1662 bags) with 2.1% culture positivity, (2) after processing for cryopreservation (1039 bags) with a further 1.1% cultures positive, and (3) after thawing at the time of reinfusion (1209 bags) of which 2.2% were culture positive. There were no culture positive specimens obtained from any peripheral blood progenitor cell products. The vast majority of the 85 culture positive specimens obtained from marrow were skin flora (89%) and 35% of all positive harvest specimens remained positive following processing and freezing. At least 36% of culture positive specimens were thought to have arisen as a result of exogenous contamination of blood culture bottles. Potentially pathogenic enteric organisms were present in nine (0.2%) specimens and infusion of these organisms occurred in four cases. A further seven patients were reinfused with marrow culture positive for skin organisms. No adverse clinical sequelae were noted following infusion of any contaminated products. However, clinical decision making continues to be influenced by culture results and multistage microbial culture continues to be of value in the management of our marrow recipients.