Early outcomes after definitive chemoradiation therapy with Vienna/Venezia hybrid high-dose rate brachytherapy applicators for cervical cancer: A single-institution experience.

PURPOSE: The Vienna and Venezia (Elekta) are hybrid intracavitary/interstitial brachytherapy (BT) applicators for cervical cancers unsuitable for intracavitary BT alone to improve target coverage or reduce critical organ dose. There is limited outcome data with the use of these applicators outside published experience of the EMBRACE group. We report feasibility and early outcomes with the use of these hybrid applicators at our institution. METHODS AND MATERIALS: Hybrid applicators were used to treat 61 patients with cervical cancer from November 2011 to December 2019. Indications for hybrid applicator use were involvement of the vagina in 10 patients (16%), residual central or parametrial disease in 46 patients (75%), and a narrow introitus in 5 patients (9%). Toxicities were graded using the CTCAE v4.0. Outcomes were assessed with the Kaplan-Meier method. RESULTS: Median follow-up was 16 months (IQR 9-32 mos). Median HRCTV volume was 31.6 cm3 (IQR 25-48 cm3). Median HRCTV D90 was 86.1 Gy (IQR 84.3-88.0 Gy). In 54 patients with follow-up PET/CT at 3 months, complete initial imaging response locally was seen in 46 patients.Estimated 12-month Kaplan-Meier overall survival, locoregional control, distant control, and recurrence-free survival estimates were 86.9%, 80.6%, 73.8%, and 65.9%, respectively. The 12-month incidence of Grade 3+ GI/GU chronic toxicities was 5.7%, consisting of vesicovaginal fistula, rectovaginal fistula, and ureterovesical fistula. CONCLUSIONS: Our single-institution data support the use of the hybrid applicators, as an alternative to traditional BT applicators when clinically warranted. Use of hybrid applicators is feasible with adequate coverage of disease in the vagina and parametrium.

Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells.

COPD is a prevalent lung disease with significant impacts on public health. Affected airways exhibit pulmonary neutrophilia and consequent secretion of pro-inflammatory cytokines and proteases, which result in lung emphysema. Probiotics act as nonspecific modulators of the innate immune system that improve several inflammatory responses. To investigate the effect of Lactobacillus rhamnosus (Lr) on cigarette smoke (CS)-induced COPD C57Bl/6 mice were treated with Lr during the week before COPD induction and three times/week until euthanasia. For in vitro assays, murine bronchial epithelial cells as well as human bronchial epithelial cells exposed to cigarette smoke extract during 24 hours were treated with Lr 1 hour before CSE addition. Lr treatment attenuated the inflammatory response both in the airways and lung parenchyma, reducing inflammatory cells infiltration and the production of pro-inflammatory cytokines and chemokines. Also, Lr-treated mice presented with lower metalloproteases in lung tissue and lung remodeling. In parallel to the reduction in the expression of TLR2, TLR4, TLR9, STAT3, and NF-κB in lung tissue, Lr increased the levels of IL-10 as well as SOCS3 and TIMP1/2, indicating the induction of an anti-inflammatory environment. Similarly, murine bronchial epithelial cells as well as human bronchial epithelial cells (BEAS) exposed to CSE produced pro-inflammatory cytokines and chemokines, which were inhibited by Lr treatment in association with the production of anti-inflammatory molecules. Moreover, the presence of Lr also modulated the expression of COPD-associated transcription found into BALF of COPD mice group, i.e., Lr downregulated expression of NF-κB and STAT3, and inversely upregulated increased expression of SOCS3. Thus, our findings indicate that Lr modulates the balance between pro- and anti-inflammatory cytokines in human bronchial epithelial cells upon CS exposure and it can be a useful tool to improve the lung inflammatory response associated with COPD.

Oral feeding of Lactobacillus bulgaricus N45.10 inhibits the lung inflammation and airway remodeling in murine allergic asthma: Relevance to the Th1/Th2 cytokines and STAT6/T-bet.

Asthma is a chronic disease with impacts on public health. It affects the airways causing pulmonary inflammation mediated by CD4 T cells type Th2, eosinophilia, mucus hypersecretion, and elevated IgE. The unbalance between cytokines and transcription factors is an important feature in asthma. Probiotics has gaining highlight as a therapy for chronic diseases. Thus, we investigate the Lactobacillus bulgaricus (Lb) effect in murine allergic asthma. BALB/c-mice were sensitized to ovalbumin (OA) on days 0 and 7 and were challenged from day 14-28 with OA. Mice received Lb seven days prior to sensitization and it was kept until day 28. The Lb attenuated the eosinophils infiltration, mucus and collagen secretion, IgE production, pro-inflammatory cytokines, TLR4 expression, GATA3, STAT6 and RORγt in lung. Otherwise, Lb increased the anti-inflammatory cytokines, the T-bet and foxp3. Finally, Lb attenuated the allergic asthma-induced inflammation and airway remodeling by interfering on Th1/Th2 cytokines and STAT6/T-bet transcription factors.

Biomechanical comparison of four methods of repair of the Achilles tendon: a laboratory study with bovine tendons.

We tested four types of surgical repair for load to failure and distraction in a bovine model of Achilles tendon repair. A total of 20 fresh bovine Achilles tendons were divided transversely 4 cm proximal to the calcaneal insertion and randomly repaired using the Dresden technique, a Krackow suture, a triple-strand Dresden technique or a modified oblique Dresden technique, all using a Fiberwire suture. Each tendon was loaded to failure. The force applied when a 5 mm gap was formed, peak load to failure, and mechanism of failure were recorded. The resistance to distraction was significantly greater for the triple technique (mean 246.1 N (205 to 309) to initial gapping) than for the Dresden (mean 180 N (152 to 208); p = 0.012) and the Krackow repairs (mean 101 N (78 to 112; p < 0.001). Peak load to failure was significantly greater for the triple-strand repair (mean 675 N (453 to 749)) than for the Dresden (mean 327.8 N (238 to 406); p < 0.001), Krackow (mean 223.6 N (210 to 252); p < 0.001) and oblique repairs (mean 437.2 N (372 to 526); p < 0.001). Failure of the tendon was the mechanism of failure for all specimens except for the tendons sutured using the Krackow technique, where the failure occurred at the knot. The triple-strand technique significantly increased the tensile strength (p = 0.0001) and gap resistance (p = 0.01) of bovine tendon repairs, and might have advantages in human application for accelerated post-operative rehabilitation.

Effects of enoxaparin preparations on thrombin generation and their correlation with their anti-FXa activity.

OBJECTIVE: Anticoagulant effect of LMWHs is monitored by anti-factor Xa (anti-FXa) activity assay. Since this test has several limitations, the aim of this study was to explore the activity of two LMWHs by thrombin generation assay (TG, which presents an overall picture of hemostatic balance) and its correlation with their anti-FXa activity. METHODS: In an open-label, randomized cross-over study, 40 mg of two enoxaparins, the original branded formulation (R) and another one, also marketed in Argentina (T), were daily injected subcutaneously, for 7 days, to 20 healthy volunteers, with a 7-day washout interval. Blood samples were collected before treatment and 180 minutes after the injection on days 3 and 7. TG in platelet-poor plasma activated with tissue factor was assessed by lag time (LT), time to peak (TTP), peak (PTG), and endogenous thrombin potential (ETP). Anti-FXa and anti-FIIa activities, free tissue factor pathway inhibitor (free TFPI), tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and euglobulin lysis time (ELT) were also assayed. RESULTS: The mean (SD) anti-FXa (UI/ml) for T and R increased on days 3 and 7. LT and TTP were significantly prolonged by both LMWHs, with no differences between them. The mean ETP (nmol/L) for T and R at 3 and 7 days after treatment were significantly reduced when compared with basal values (p = 0.001 for all). On day 3, a significant correlation was shown between the variables describing TG and anti-FXa for T and R, without differences between them, for LT (r: 0.516 and 0486), ETP (r: 0.532 and 0.574), PEAK (r: 0.482 and 0.501), and TTP (r: 0.577 and 0.503), respectively. This correlation was also significant on day 7. Anti-FIIa activity and free TFPI increased significantly at 3 and 7 days for both LMWHs, without differences between them. R and T decreased ELT and PAI-1, but had no effect on t-PA. There were no differences between both LMWHs in routine hemostatic tests. No adverse events were reported. CONCLUSIONS: Correlation between TG and anti-FXa activity was good. Both enoxaparins induced similar change of coagulation parameters, with a significant increase in fibrinolytic activity.

Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease: role of MyD88 adaptor molecule and interleukin-12/interferon-gamma axis.

BACKGROUND: Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. OBJECTIVE: We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice. METHODS: Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. RESULTS: Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia, type-2 cytokines secretion, airway hyper-reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1-affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL-12/IFN-gamma axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. CONCLUSION: Toll-like receptor 4 agonists co-adsorbed with allergen onto alum down-modulate allergic lung disease and prevent the development of polarized T cell-mediated airway inflammation.

Suppression of asthma-like responses in different mouse strains by oral tolerance.

In this study we examined the effect of oral antigen (Ag) administration on the development of experimental asthma in different mouse strains. We selected BALB/c, BP2, CBA/Ca interleukin (IL)-5 transgenic, and BALB/c T-cell receptor-delta-deficient mouse strains because they exhibit different aspects of the asthma syndrome. Mice exposed to 1% ovalbumin (OVA), dissolved in the drinking water for 5 consecutive days, became unresponsive to subsequent immunogenic OVA challenges. This regimen of OVA administration induced Ag-specific unresponsiveness in all mouse strains tested, including gammadelta-deficient mice that are said to be resistant to tolerance induction. The Ag-specific unresponsiveness was characterized by reduced (almost absent) airway eosinophilic inflammation, airway hyperreactivity, and mucus production; also by low levels of T helper (Th) 2-type cytokines in bronchoalveolar lavage fluid, and decreased immunoglobulin (Ig) G1 and IgE OVA-specific antibody production. The unresponsive state was not associated with increased levels of the suppressive cytokines IL-10 and transforming growth factor (TGF)-beta or with immune deviation toward the Th1 pathway due to increased levels of interferon-gamma and IL-12. Moreover, treatment with anti- TGF-beta antibodies did not abrogate oral tolerance. Oral Ag administration was quite effective in suppressing the development of key features of asthma when initiated after primary immunization (Day 0) or after booster (Day 7), but not after challenge (Day 14) when it increased allergic responses. Collectively, our findings show for the first time the beneficial and detrimental effects of oral Ag administration on the development of experimental asthma.

A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team.

OBJECTIVE: The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 300 assessed the clinical efficacy and safety of combination zidovudine/lamivudine (ZDV/3TC) compared with either didanosine (ddI) alone or combination ZDV/ddI. STUDY DESIGN: Children with symptomatic human immunodeficiency virus (HIV) infection, 6 weeks through 15 years of age, were stratified according to age and randomly assigned to receive ddI, ZDV/3TC, or ZDV/ddI. The primary endpoint was time to first progression of HIV disease or death. Enrollment in the ZDV/ddI arm stopped after 11 months on the basis of results of PACTG Protocol 152, but blinded follow-up continued. RESULTS: For the 471 children who could be evaluated, the median age was 2.7 years, median CD4 cell count was 699 cells/mm3, and median log10 HIV RNA was 5.1/mL. Median follow-up was 9.4 months. Patients receiving ZDV/3TC had a lower risk of HIV disease progression or death than those receiving ddI alone (15 vs 38 failures, P = .0006) and a lower risk of death (3 vs 15 deaths, P = .0039). Weight and height growth rates, CD4+ cell counts, and RNA concentrations showed results favoring ZDV/3TC. For patients concurrently randomized to all 3 treatment arms, both ZDV/3TC and ZDV/ddI recipients had lower risk of HIV disease progression than those who received ddI alone (P = .0026 and P = .0045). CONCLUSIONS: Combination therapy with either ZDV/3TC or ZDV/ddI was superior, as determined by clinical and laboratory measures, to monotherapy with ddI.

[The family planning program of the Secretaría de Salubridad y Asitencia in the border states]. / El Programa de Planificación Familiar de la Secretaría de Salubridad y Asistencia en los estados fronterizos.

PIP: All available data to date indicate that the Family Planning Program of the Public Health Department, together with the rest of the Health Institutions which offer this type of service are having great success at the national level and, consequently, in the border states. The Public Health Department Program and the Programs of the Institutions as a whole are enrolling approximately 15% of the eligible couples/year, this number compares very favorably with that reported internationally. The rapid progress observed in the rural areas has been particularly stimulating, especially if we consider the fact that it is this area that the greatest resistance was expected. At the present time, one of the prime activities of the Public Health Department is to extend the Program to a greater number of rural communities through an established network of community promoters. There is a clear difference in the yield, extension, etc. between the different health units within the same state. This variation includes the border states as well. The directed efforts to understand and detect these differences systematically are still being studied. Presently we can state that the coverage reached by the Program has not yet begun to stagnate or indicate negative growth, although there is some indication of this in the urban areas. Acceptor characteristics point to the necessity of extending the Program to an economically weak population and not to restrict it to the privileged people. This is supported by the results obtained in a National Contraceptive Prevalence Study done by the Coordination of the National Program for Family Planning, which shows that 60% of couples in urban areas use contraceptive methods, 20% of rural couples, and 40% at the national level. These numbers are equal or even greater in the border states. (author's modified)^ieng

[Assessment of the promotion component in the postpartum/postabortion program]. / Evaluación del componente de promoción en el programa postparto/postaborto.

PIP: To study the low acceptance rate of contraception, the authors investigated the postpartum postabortum program of family planning in 8 hospitals run by the Mexican Ministry of Health. During 1 week all patients, 502 women who were leaving the hospital were interviewed; the personnel in charge of family planning were also interviewed. The number of acceptors leaving the hospital went from 1% of patients in Hermosillo to 47% in the General Hospital, a rate of acceptance much lower than that observed with other programs. Sociocultural characteristics of patients were very similar in all hospitals, and acceptance of IUDs was much greater than acceptance of the pill. In all hospitals, promotion of contraception consisted of a talk given to groups of patients and never to individuals; in most hospitals there were no other possibilities to receive contraceptive information. Most patients, either before or after the talk, still equated family planning with better education for children and better social conditions for the family; very few mentioned the health of mothers and children. 4% of patients did not know what contraceptives were available at the hospital even after the talk; many patients stated that the type of presentation and the vocabulary used were too difficult. Only 4% left the hospital with an adequate knowledge of both oral contraception and the IUD. Duration of the talk went from 7-39 minutes, depending on the hospital. The personnel delivering the talk were not specifically prepared for that purpose, and many times failed to answer questions or to expound on important aspects of contraception, such as side effects or contraindications. No teaching materials were available and even the meeting rooms were inadequate. It is obvious that postabortum postpartum programs of family planning should be restructured and reorganized, personnel should be trained, patients should receive individual attention, husbands should be encouraged to participate, and simple, inexpensive teaching materials, such as slides and prints, should be made available.^ieng

[Characteristics of women participating in the family planning program of the Direccion General de Atencion Medica Materna Infantil y Planificacion Familiar de la SSA]. / Perfil de las usuarias del Programa de Planificación Familiar de la Dirección General de Atención Médica Materno Infantil y Planificación Familiar de la SSA.

PIP: It is evident that since the period 1973-4, some important changes have occurred with regard to the age, number of living children, and educational status of new acceptors within the family planning program of the Secretaria de Salubriad y Asistencia. While the 1973-4 acceptors were older, had more children, and had more education, the 1976 acceptors were younger, had less education, and had a number of children similar to the population at large. It is interesting to note that 1976 rural acceptors exhibit the same fertility levels as those acceptors of the 1973-4 urban programs, although as a whole, they are younger and less educated. It is possible that through the same legitimization process, accelerated by communication and motivation campaigns, it will shortly be possible for the rural program to recruit acceptors with fewer children. (author's modified)^ieng

Recent trends in contraceptive use in Mexico.

In 1973 the Mexican government changed its official position on family planning from one of neurtality to one of support. Prior to that time, family planning activities had been limited to the commercial sector and two private programs. As a result of the new policy, all major official health programs began organizing family planning activities. While about the same number of couples were served by the private programs in 1976 as in 1973, the commercial sector grew at over 10 percent per year and official coverage expanded around fivefold. It is estimated that the proportion of eligible women protected by contraception doubled and that the birth rate fell from 43-44 in 1973 to 37-40 by the end of 1976.

[Evaluation of the voluntary family planning program of the Instituto Mexicano del Seguro Social. I. Generalities, socioeconomic and demographic characteristics]. / Evaluación del programa de planificación familiar voluntaria del Instituto Mexicano del Seguro Social. I. Generalidades: características socioeconómicas y demográficas

PIP: The Voluntary Family Planning Program (PPFV) of the Mexican Institute of Social Security (IMSS), established in 1972, provides clinic services for clients both with or without health insurance. From 1972 to 1976 PPFV has provided services to 998,000 acceptors. A PPFV-IMSS pilot study done from November 1974 to April 1975 showed that 53% of the acceptors are between 25 to 34 years old, with an average of 29.9. About 22% are in the age group 15-24 years; 25% are older than 34. 26.4% have 2 or less living children; 58.3% have less than 4 living children. 23% desire more children, the mean being 0.4 children. 7.7% had no formal education; 38.7% had completed primary education. Average family income is 3000 pesos per month. Before entering the program, 43% had used some contraceptive method, mainly oral contraceptives. These acceptor characteristics are the common ones observed in the initial phases of any family planning program, e.g., the acceptors are older, high parity women with more education and higher incomes. IMSS data, and data collected by the Social Security Administration, indicate that marginal groups of the population have not been reached yet. The PPFV-IMSS program has been relatively successful in covering high risk women, but low risk women and women with little education and low income continue to be underrepresented. There may be 1 million sexually active teenagers unprotected by contraception. The health and demographic impacts the program hopes to attain may be lessened by the percentage of women who had already been practicing contraception prior to entering the program. The program should redouble its efforts to attract acceptors who have never practiced contraception.^ieng

[Experience with the intraterine device in the Programa de Planificacion Familiar de la Secretaria de Salubridad y Asistencia 1973-1974]. / La experiencia con el dispositivo intrauterino en el Programa de Planificación Familiar de la Secretaría de Salubridad y Asistencia 1973-1974

PIP: The present study explores the experience obtained with the Lippes Loops C and D in the family planning program of the Secretaria de Salubridad y Asistencia (Ministry of Health) of Mexico. The patterns observed are sufficiently similar to those reported for the majority of other countries for which data are available that it would appear that no special conditions affecting use of this method exist in Mexico. The study is viewed as having utility for practicing physicians as it provides information on relative frequency of temporary and definitive use terminations, relative frequency of method failure, expulsion, withdrawals for various reasons, and the specific groups of women most disposed to each type of event. The variables studied in this representative sample of acceptors are duration of method use, number of pregnancies prior to acceptance, number of children living, age, and educational level. (author's)^ieng