Particle-mediated delivery of cytokines for immunotherapy

The ability of cytokines to direct the immune response to vaccination, infection and tumors has motivated their use in therapy to augment or shape immunity. To avoid toxic side effects associated with systemic cytokine administration, several approaches have been developed using particle-encapsulated cytokines to deliver this cargo to specific cell types and tissues. Initial work used cytokine-loaded particles to deliver proinflammatory cytokines to phagocytes to enhance antimicrobial and antitumor responses. These particles have also been used to create a cytokine depot at a local site to supplement prophylactic or antitumor vaccines or injected directly into solid tumors to activate immune cells to eliminate established tumors. Finally, recent advances have revealed that paracrine delivery of cytokines directly to T cells has the potential to enhance T-cell mediated therapies. The studies reviewed here highlight the progress in the last 30 years that has established the potential of particle-mediated cytokine immunotherapy.     

GENETIC CONTROL OF IMMUNOLOGICAL RESPONSIVENESS IN GUINEA PIGS TO 2,4-DINITROPHENYL CONJUGATES OF POLY-L-ARGININE, PROTAMINE, AND POLY-L-ORNITHINE

The ability of guinea pigs to respond immunologically to dinitrophenyl (DNP)-poly-L-arginine, DNP-protamine, DNP polyornithine, and to unsubstituted poly-L-arginine and protamine is linked to the presence of the poly-L-lysine gene. This gene has previously been demonstrated to control the immune response of guinea pigs to poly-L-lysine, to a copolymer of L-glutamic acid and L-lysine and to haptenic derivatives of these materials.Although the ability to respond to each of these highly charged compounds is linked to the presence of the poly-L-lysine gene, the cellular immune responses to these antigens is highly individually specific.     

Nationwide antimicrobial susceptibility survey of Neisseria gonorrhoeae isolates in Japan

In a nationwide antimicrobial susceptibility survey of 494 Nesseria gonorrhoeae isolates collected from February 2008 to December 2009 in 3 regions of Japan, 112 (22.7%) were collected from western Japan (Kinki, Chugoku, Shikoku, and Kyushu), 277 (56.1%) from mid-eastern Japan (Kanto), and 105 (21.1%) from eastern Japan (Tokai, Hokuriku, Koushinetsu, Tohoku, and Hokkaido). Resistance to ciprofloxacin (CPFX) was 72.8%, to penicillin G (PCG) 19.8%, and to tetracycline (TC) 18.2%. Intermediate resistance to CPFX was 1.8%, to PCG 73.7%, and to TC 43.7%. These results indicate that both types of resistance to the 3 agents were very high. Intermediate resistance to cefixime (CFIX) was 38.1% and to cefozidim (CDZM) 13.4%. Resistance to CFIX was only 0.4% and to CDZM 0%. Susceptibility to azithromycin was 96.6%, to ceftriaxone 99.8%, and to spectinomycin 100%. No significant difference in resistance was seen to different antimicrobial agent classes tested in the 3 regions, although intermediate resistance to CFIX in western Japan was significantly higher than in mid-eastern Japan.     

'Original antigenic sin', T cell memory, and malaria sporozoite immunity: an hypothesis for immune evasion

Prior to any exposure to malaria, most adults have T cells specific for malaria parasites and various malaria proteins. The protein for which this has been shown more than any other is the circumsporozoite protein (CSP) of Plasmo-dium falciparum. These T cells can be present in high frequency and appear to have arisen through exposure to other (non-malaria) organisms. Although T cells are thought to provide protection against sporozoites, these T cells specific for cross-reactive organisms are clearly unable to protect against malaria, and may be preferentially expanded following exposure to malaria sporozoites. Thus, cross-reactive organisms have the potential to skew the repertoire of sporozoite-induced T cells and affect the induction of protective immunity. This is analogous to the concept of 'original antigenic sin' whereby prior exposure to one strain of influenza virus was shown to be able to divert the antibody response to a second challenging strain to focus on the shared (cross-reactive) epitopes.     

Thermoregulation and aging.

Worldwide climate changes, bringing long-lasting higher and lower extremes of temperature, are leading to an increased mortality rate in elderly people due to cardiocirculatory dysfunction. The ability of young adults to make physiological adjustments when exposed to low or high temperatures decreases with age. The purpose of this literature review is to assess the dysfunctions occurring in the elderly as a result of their reduced responsiveness to thermal stress. Physiological responses to cold environment induce a reversible plasma water shift from the intravascular to the interstitial and intracellular level due to peripheral vasoconstriction. This phenomenon occurs on exposure to cold water or air and even during facial cooling by a cold wind. Above-normal temperatures induce a reduction in intravascular water due to sweating. Older people are less able to cope with the increased viscosity of blood and are thus more liable to suffer a cardiocirculatory accident.     

Gender differences in health perceptions and meaning in persons living with heart failure

OBJECTIVE: The goal of this study was to determine whether gender differences exist in health perceptions, psychosocial adjustment to illness, and concerns related to illness in patients with heart failure (HF). DESIGN: Thirty-two patients (50% women) from a single outpatient HF clinic were asked to complete standardized tools to assess health perceptions and psychosocial adjustment to illness. Open-ended questions were used to obtain data on concerns related to HF. RESULTS: The women had higher health perceptions than men did; they also demonstrated better psychosocial adjustment to illness. The qualitative data further suggest that women ascribed more positive meanings to their illness than men did. CONCLUSION: The current study underscored the importance of gender differences in health perceptions related to HF. Patient teaching and counseling can be tailored to address the gender-specific concerns of men and women suffering with this condition to improve patient outcomes.     

True and false contraindications to vaccines

Nowadays, the awareness of risks related to infectious diseases has decreased, whereas THE perception of risks related to vaccination is growing. Therefore, it may be difficult for health care providers to convince people of the importance of vaccination and adherence to the immunisation schedule.Selected situations that might raise uncertainties about vaccine recommendations are discussed in order to help health care providers to identify real and perceived contraindications to vaccines, and cases to be referred to specialised pre-vaccination consultation due to an increased risk of adverse events to vaccines.     

Antibiotic resistance of Neisseria species in Iran: A systematic review and meta-analysis

Objective: To estimate the prevalence of antibiotic resistance of Neisseria species in Iran. Methods: A systematic and electronic search using relevant keywords in major national and international databases was performed until 6th July, 2018 in order to find studies reporting the prevalence of antibiotic resistance of Neisseria species in Iran. Results: A total of nine studies were found to be eligible based on predefined inclusion and exclusion criteria. Our analysis indicated that the prevalence of Neisseria gonorrhoeae resistance to different antibiotics was as follows: 66.9% to penicillin, 59.1% to ciprofloxacin, 11.1% to ceftriaxone, 21.6% to spectinomycin, 13.8% to cefixime, 82.4% to co-trimoxazole, 52.7% to tetracycline, 29.9% to gentamicin, 87.5% to ampicillin, 11.1% to azithromycin, 2.2% to chloramphenicol, 50.1% to cefepime and 50.0% to vancomycin. Antimicrobial resistance rates of Neisseria meningitidis was as follows: 30.0% to penicillin, 33.3% to amoxicillin, 33.3% to cephalexin, 55.6% to ampicillin and 0.0% to ciprofloxacin, ceftriaxone, cefotaxime, amikacin, co-trimoxazole, gentamicin, kanamycin, chloramphenicol and ceftizoxime. Conclusion: Neisseria gonorrhoeae and Neisseria meningitidis isolates of Iran show resistance to different types of antibiotics. Therefore, care should be exercised for the use of penicillin, ciprofloxacin, co-trimoxazole, tetracycline, gentamicin, ampicillin, cefepime and vancomycin for gonococcal infections, and also with respect to the use of penicillin, amoxicillin, ampicillin and cephalexin for meningococcal infections in Iran.     

Acquisition of multiple drug resistance by CCRF-CEM cells selected for different degrees of resistance to vincristine

We studied the acquisition of multiple drug resistance to several "natural product" drugs by cultured human leukemic lymphoblasts selected for increasing resistance to vincristine (VCR). Three apparent types of cross-resistance patterns could be distinguished: specific, pleiotropic, and mixed. Cross-resistance to vindesine developed in parallel with VCR resistance, appearing at the lowest levels of VCR resistance (approximately fivefold). Vinblastine resistance did not become noticeable until VCR resistance was higher (approximately equal to 50-100-fold). Cross-resistance resistance to three other tubulin-binding agents developed in a different pattern, however. While cross-resistance to maytansine was seen in cells of intermediate (approximately equal to 50-fold) resistance to VCR, colchicine cross-resistance occurred only in cells that were highly resistant to VCR (approximately equal to 500-fold). Even at the highest level of VCR resistance (approximately equal to 600-fold), complete sensitivity to podophyllotoxin was retained. Conversely, cross-resistance to the epipodophyllotoxins , teniposide and etoposide, semisynthetic derivatives of podophyllotoxin, was seen in cells that were greater than 50-fold resistant to VCR. The same pattern obtained for the anthracyclines, doxorubicin and daunorubicin. We conclude that resistance to low concentrations of VCR does not uniformly confer cross-resistance to other classes of natural product drugs.     

Insulin secretion by rat islet isografts of a defined endocrine volume after transplantation to three different sites

Summary We have analysed the graft function of rat islet isografts of identical and well-defined endocrine volumes after transplantation to three different sites (kidney, liver and spleen). Graft endocrine mass was determined by measuring the total islet volume prior to transplantation and was chosen to be similar to the endocrine volume in the normal adult rat pancreas. Graft function was tested in unanaesthetized, unstressed rats by the responses to glucose infusion and to a meal. All transplanted animals returned to normoglycaemia within one week after transplantation. At one month, basal glucose and insulin levels were similar to controls in rats with grafts to the spleen, but higher in rats with grafts to the kidney or liver. Irrespective of the transplantation site, recipients had higher glucose and lower insulin levels than controls in response to glucose infusion, but in response to a meal these differences from normal were less obvious. Finally, recipients showed both an acute insulin response to glucose infusion as well as a pre-absorptive insulin release after food ingestion, irrespective of the transplantation site. Our findings indicate that the insulin response to glucose infusion and to a meal is quantitatively reduced, but qualitatively intact after transplantation to the kidney, liver or spleen.     

The American Health Care System Is Broken. Part 7: How Can We Fix It?

Previous articles have outlined the many problems that confront America in trying to humanely and efficiently deliver health care to our citizens. First among these is that health care is unaffordable for too many. This final article describes how to expand coverage to all Americans and identifies many specific areas in which changes can be made to both improve care and lower costs. There are many ways to reduce the cost of medications, to improve hospital care while lowering costs, to eliminate “surprise” medical bills, and to cut down fraud and waste. The socioeconomic factors that contribute heavily to our poor health outcomes must be addressed.     

Bangkok 2004. Youth: too often missing from the response

Responses to HIV/AIDS need to recognize the diversity of youth and need to be inclusive of youth. In his presentation to a plenary session of the XV International AIDS Conference in Bangkok on 14 July 2004, Raoul Fransen explains why it is important to involve youth in policy-making and at all stages of program development and implementation. The presentation emphasizes the need to ensure that young people are able to make choices concerning their sexuality, and are provided with the information and support necessary to enable them to make intelligent choices.     

Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol.

The acute and chronic neurologic effects of ethanol appear to be due to its interaction with neural cell membranes. Chronic exposure to ethanol induces changes in the membrane that lead to tolerance to the effects of ethanol. However, the actual membrane changes that account for tolerance to ethanol are not understood. We have developed a model cell culture system, using NG108-15 neuroblastoma-glioma hybrid cells, to study cellular tolerance to ethanol. We have found that adenosine receptor-stimulated cAMP levels increased markedly upon acute exposure to ethanol. However, the cells became tolerant to ethanol, since chronically treated cells required ethanol to maintain normal adenosine-stimulated cAMP levels. Moreover, the cells appeared to be dependent on ethanol, as evidenced by reduced adenosine-stimulated cAMP levels in the absence of ethanol. Recovery occurred after ethanol was withdrawn. These cellular changes appear to parallel the clinical events of acute ethanol intoxication, tolerance, and dependence.     

Genetic and environmental influences on the rate of progression to alcohol dependence in young women

Background: The development of alcohol dependence (AD) involves transitions through multiple stages of drinking behaviors and is shaped by both heritable and environmental influences. We attempted to capture this dynamic process by characterizing genetic and environmental contributions to the rate at which women progressed through 3 significant transitions along the pathway to AD: nonuse to initiation, initiation to onset of first alcohol‐related problem, and first problem to onset of AD. Methods: The sample consisted of 3,546 female twins from the Missouri Adolescent Female Twin Study. Participants ranged in age from 18 to 29 years. Retrospective reports of alcohol use histories were collected by telephone diagnostic interview and transition times between drinking milestones were coded ordinally. Standard genetic analyses were conducted in Mx to derive a trivariate model that provided estimates of genetic and environmental influences that were common as well as specific to the 3 transition times. Results: Heritable influences were found for rate of progression across all 3 transitions, accounting for 30 to 47% of the variance in transition times. Shared environmental contributions were evident only in rate of progression from nonuse to initiation (i.e., age at first drink). Heritable contributions to the rate of movement through successive drinking milestones were attributable to a common factor, whereas environmental influences were transition‐specific. Conclusions: The current study is unique in its use of a genetically informative design to document the rate of movement between drinking milestones in a female sample and to examine genetic contributions to multiple transition times over the course of AD development. Results indicate that an earlier report of heritability for males in rate of progression from regular drinking to AD generalizes to women and to other alcohol stage transitions. Findings also suggest the need to consider stage‐specific environmental contributions to alcohol outcomes in developing interventions.     

Varicella vaccine potency and stability during transport and delivery

Oka varicella vaccine was developed to confer active immunity to varicella-zoster virus (VZV) in immunocompromized and immunocompetent children. It is now used to prevent varicella in about 20 million people worldwide. Although VZV infectivion is relatively unstable compared to other viruses, cell-free virus is stabilized and lyophilized vaccine has been developed. Virus titers were evaluated in vaccine distributed to six clinics in 5 years. Yearly mean virus titers at the vaccine producer were 42,000-67,000 plaque-forming units per dose, corresponding to Oka varicella vaccine (Zostavax) used to prevent zoster and postherpetic neuralgia by Oxman et al. Virus titer was found to be stable during delivery to clinics. Virus titers of varicella vaccine were equivalent to Zostavax and vaccine delivered to clinics had enough virus titer to confer active immunity to VZV in this study.     

Antimicrobial susceptibility of Bacillus anthracis

22 Bacillus anthracis isolates were tested for susceptibility to 27 antimicrobial agents by agar dilution. All isolates were sensitive to penicillins and did not produce beta-lactamase. Although all isolates were sensitive to cefazolin, cephalothin, cephradine and cefoperazone 19 isolates were resistant to cefuroxime, 18 to cefotaxime, 18 to ceftizoxime, 9 to ceftriaxone and 21 to ceftazidime. All isolates were also found to be sensitive to other antimicrobials tested. The new antimicrobial agents, ofloxacin and ciprofloxacin showed very good activity with MICs of 0.03-0.06 mg/l.     

广州地区5年间耐多药结核分枝杆菌药物敏感试验结果分析

目的总结耐多药结核分枝杆菌药物敏感试验结果,为制定耐多药治疗方案提供依据。方法回顾分析过去5年广州市胸科医院收治的肺结核患者,其中痰液培养结核分枝杆菌药物敏感性试验结果为耐多药的菌株共605株,按年度和除异烟肼和利福平外的其他抗结核药物的种类进行统计,比较分析,分析各种抗结核药物的耐药率以及对比五年间耐药率的变化情况。结果阿米卡星的耐药率16.86%,克拉霉素的耐药率12.89%,对氨基水杨酸异烟肼的耐药率25.29%。乙胺丁醇的耐药率63.64%,链霉素的耐药率87.27%和利福布汀的耐药率73.06%。左氧氟沙星的耐药率41.15%,莫西沙星的耐药率40.49%,丙硫异烟胺的耐药率42.81%。结论在广州地区中,阿米卡星、克拉霉素和对氨基水杨酸异烟肼的耐药率比较低。     

The Global TB Drug Facility: innovative global procurement.

The Global TB Drug Facility (GDF) is a new initiative to increase access to high quality tuberculosis drugs. The GDF, a project of the Global Partnership to Stop TB, is managed by its secretariat, in the World Health Organization (WHO), Geneva. It aims to provide tuberculosis drugs to treat up to 11.6 million patients over the next 5 years and to assist countries to reach the WHO global TB control targets by 2005. The GDF was launched on 24 March 2001. Six rounds of applications have been completed, with 46 countries and non-governmental organisations (NGOs) approved for support. The GDF is not a traditional procurement mechanism. It has adopted an innovative approach to the supply of drugs, by linking demand for drugs to supply and monitoring, using partners to provide services, using product packaging to simplify drug management and linking grants to TB programme performance. This paper describes the GDF operational procedures and experience gained so far. Key achievements to date are also outlined, including the creation of a flexible supply system to meet differing programme needs, rapid establishment of procedures, reduction in TB drug prices--a catalyst for DOTS expansion in countries, standardisation of products, and collaboration with partners. The GDF is flexible enough to meet the needs of countries with a TB burden. The GDF experience could be used as an example for global procurement of drugs and commodities for other diseases, such as HIV/AIDS and malaria. In the future it is likely that the GDF will expand to include second-line drugs and diagnostic materials for TB and could assist other partnerships to develop similar mechanisms and facilities to meet country needs.