Therapeutic Phages as Modulators of the Immune Response: Practical Implications.

While the medical community awaits formal proof of the efficacy of phage therapy, as is required by evidence-based medicine, existing data suggest that phages could also be applied based on their non-antibacterial action, especially phage-mediated immunomodulation. Promising avenues have been revealed by findings indicating that phages may mediate diverse actions in the immune system, while the list of phages able to dampen the aberrant immunity associated with a variety of disorders continuously grows. Here we summarize what is known in this field and possible options for the future. While available data are still scarce and preliminary, it appears that "phage repurposing" is worthy of more research, which could reveal new perspectives on applying phage therapy in contemporary medicine.

Pharmacokinetic and Pharmacodynamic Obstacles for Phage Therapy From the Perspective of Clinical Practice.

Bacteriophages present unique features that enable targeted killing of bacteria, including strains resistant to many antibiotics. However, phage pharmacokinetics and pharmacodynamics constitute much more complex and challenging aspects for researchers than those attributable to antibiotics. This is because phages are not just chemical substances, but also biological nanostructures built of different proteins and genetic material that replicate within their bacterial hosts and may induce immune responses acting as simple antigens. Here, we present a few examples of how primary general assumptions on phage pharmacokinetics and pharmacodynamics are verified by current preclinical and clinical observations, leading to conclusions that may not be obvious at first but are of significant value for the final success of phage therapy in humans.

Laparoscopic sacrocolpopexy for neovaginal prolapse in a patient after male-to-female sex reassignment surgery.

INTRODUCTION: Male / female sex reassignment surgery is performed on transsexuals, and includes removal of the male external genitalia, and creation of the neovagina from the skin of the penis, usually allowing sexual intercourse (1, 2). The incidence of the prolapse of the neovagina is not known; however, such complication is observed relatively rarely (3, 4). the long-term outcomes of prolapse treatment in transsexual patients are not available in the literature. The purpose of this study was to demonstrate laparoscopic sacrocolpopexy to repair a neovagina prolapse in a patient after male-to-female sex reassignment surgery. MATERIALS AND METHODS: In september 2013, a laparoscopic repair was performed on a 44-year-old woman who presented a neovaginal prolapse of pelvic organ prolapse quantification (pop-q) stage iii, twenty one years after sex reassignment surgery. This condition caused painful or even indisposed intercourse. in may 2013, the patient underwent unsuccessful vaginal treatment with the suturing device. Before the initial surgery, the patient was examined with cystoscopy, urodynamics and microbiology; no pathologies were found. laparoscopic repair of the neovaginal prolapse followed the principles described previously in the natural female (5). In the supine lithotomy position, a standard multiport laparoscopic sacrocolpopexy was performed with the use of the polypropylene mesh (Artisyn® y-shaped mesh, ethicon, inc somerville, nj.) and coated polyglactin sutures. The following steps were applied: exposure of the anterior and posterior neovaginal walls; suturing the bifurcated end of the mesh to the neovagina; longitudinal incision of the parietal peritoneum and creation of a tunnel for the mesh; fixation of the proximal end of the mesh to the promontorium; and closure of the parietal peritoneum over the mesh that was placed retroperitoneally. The draining tube was left for 24 hours. RESULTS: The operation was completed successfully, with no blood loss or complications. The operative time was 115 minutes. The patient was discharged on the 2nd postoperative day. In a four-year follow-up, the patient presented significant improvement of symptoms, a small prolapse of approximate pop-q stage i, and declared performing satisfying intercourse. CONCLUSIONS: Laparoscopic sacrocolpopexy with the use of a polypropylene mesh to repair a neovaginal prolapse in transsexuals seems to be a valuable alternative to other procedures. Further observations and evaluation of a greater number of patients will be necessary to assess the actual value of the method.

Stability study in selected conditions and biofilm-reducing activity of phages active against drug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is currently a serious threat to human health, especially to people with immunodeficiency as well as patients with prolonged hospital stays and those undergoing invasive medical procedures. The ever-increasing percentage of strains characterized by multidrug resistance to widely used antibiotics and their ability to form biofilms make it difficult to fight infections with traditional antibiotic therapy. In view of the above, phage therapy seems to be extremely attractive. Therefore, phages with good storage stability are recommended for therapeutic purposes. In this work, we present the results of studies on the stability of 12 phages specific for A. baumannii under different conditions (including temperature, different pH values, commercially available disinfectants, essential oils, and surfactants) and in the urine of patients with urinary tract infections (UTIs). Based on our long-term stability studies, the most optimal storage method for the A. baumannii phage turned out to be - 70 °C. In contrast, 60 °C caused a significant decrease in phage activity after 1 h of incubation. The tested phages were the most stable at a pH from 7.0 to 9.0, with the most inactivating pH being strongly acidic. Interestingly, ethanol-based disinfectants caused a significant decrease in phage titers even after 30 s of incubation. Moreover, copper and silver nanoparticle solutions also caused a decrease in phage titers (which was statistically significant, except for the Acba_3 phage incubated in silver solution), but to a much lesser extent than disinfectants. However, bacteriophages incubated for 24 h in essential oils (cinnamon and eucalyptus) can be considered stable.

Body Loading during an Intensive Yoga Exercise Routine and a Cycle Ergometer Test.

The present study compared the effects on the cardiovascular, respiratory, and metabolic functions of the practice of an intensive yoga exercise routine called Dynamic Suryanamaskar (DSN) and a cycle ergometer test (CET) of increasing intensity. The study involved 18 middle-aged volunteers who had previously practiced DSN. The study was conducted in two series (i.e., as CET and DSN with similar intensity) until complete exhaustion. At rest (R), at the ventilatory anaerobic threshold (VAT), and at the maximum workload (ML), the variables characterizing cardiovascular, respiratory, and metabolic functions were determined. In addition, the subjective intensity of both efforts was determined using the Borg test. No functional differences were observed in the cardiovascular, respiratory, and metabolic systems at similar CET and DSN intensities. Respondents experienced less subjective workload during DSN than during CET (p < 0.001). Since DSN intensifies the activity of the cardiovascular, respiratory, and metabolic systems to a similar degree to CET both at VAT and ML, but causes less subjective fatigue, this yogic practice can be used as a laboratory exercise test and as an effective training medium.

Effects of Fasting on the Physiological and Psychological Responses in Middle-Aged Men.

Tracking changes in the body during fasting takes into account indicators of mental well-being and physiological parameters. The aim of the study was to measure psychological and physiological reactions, along with their mutual relations, caused by 8 days of water-only fasting. Fourteen men aged 35 to 60 participated in the study, divided into two groups, younger and elder. In addition to physiological parameters, psychological data were collected using four different tests. The obtained results confirmed reduction in body weight, systolic blood pressure, resting diastolic blood pressure and glucose level, and increase in resting heart rate, cortisol and ß-hydroxybutyrate concentration. However, no significant psychological changes were observed under the influence of fasting intervention. A significant interaction effect occurred for the state anxiety variable determined before and after the fasting intervention for both groups. Moreover, negative correlations between physiological (cortisol) and psychological factors of subjectively assessed stress were revealed. The only effect on cognitive ability was seen when responding to simple tasks. The study confirmed the beneficial effect of 8 days of water-only fasting on physiological variables without affecting mental well-being. The relatively high level of well-being after fasting intervention was independent of the physiological indicators of stress.

A Thorough Synthesis of Phage Therapy Unit Activity in Poland-Its History, Milestones and International Recognition.

The year 2020 marked 15 years of the Phage Therapy Unit in Poland, the inception of which took place just one year after Poland's accession to the European Union (2004). At first sight, it is hard to find any connection between these two events, but in fact joining the European Union entailed the need to adapt the regulatory provisions concerning experimental treatment in humans to those that were in force in the European Union. These changes were a solid foundation for the first phage therapy center in the European Union to start its activity. As the number of centers conducting phage therapy in Europe and in the world constantly and rapidly grows, we want to grasp the opportunity to take a closer look at the over 15-year operation of our site by analyzing its origins, legal aspects at the local and international levels and the impressive number and diversity of cases that have been investigated and treated during this time. This article is a continuation of our work published in 2020 summarizing a 100-year history of the development of phage research in Poland.

Low Immunogenicity of Intravesical Phage Therapy for Urogenitary Tract Infections.

Patients with chronic urinary and urogenital multidrug resistant bacterial infections received phage therapy (PT) using intravesical or intravesical and intravaginal phage administration. A single course of PT did not induce significant serum antibody responses against administered phage. Whilst the second cycle of PT caused a significant increase in antibody levels, they nevertheless remained quite low. These data combined with good therapy results achieved in some patients suggest that this mode of PT may be an efficient means of therapy for urogenital infections and a reliable model for a clinical trial of PT.

Potential for Phages in the Treatment of Bacterial Sexually Transmitted Infections.

Bacterial sexually transmitted infections (BSTIs) are becoming increasingly significant with the approach of a post-antibiotic era. While treatment options dwindle, the transmission of many notable BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum, continues to increase. Bacteriophage therapy has been utilized in Poland, Russia and Georgia in the treatment of bacterial illnesses, but not in the treatment of bacterial sexually transmitted infections. With the ever-increasing likelihood of antibiotic resistance prevailing and the continuous transmission of BSTIs, alternative treatments must be explored. This paper discusses the potentiality and practicality of phage therapy to treat BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Streptococcus agalactiae, Haemophilus ducreyi, Calymmatobacterium granulomatis, Mycoplasma genitalium, Ureaplasma parvum, Ureaplasma urealyticum, Shigella flexneri and Shigella sonnei. The challenges associated with the potential for phage in treatments vary for each bacterial sexually transmitted infection. Phage availability, bacterial structure and bacterial growth may impact the potential success of future phage treatments. Additional research is needed before BSTIs can be successfully clinically treated with phage therapy or phage-derived enzymes.

Isolation and Characterization of Phages Active against Paenibacillus larvae Causing American Foulbrood in Honeybees in Poland.

The aim of this study was the isolation and characterization, including the phage effect on honeybees in laboratory conditions, of phages active against Paenibacillus larvae, the causative agent of American Foulbrood-a highly infective and easily spreading disease occurring in honeybee larva, and subsequently the development of a preparation to prevent and treat this dangerous disease. From the tested material (over 2500 samples) 35 Paenibacillus spp. strains were obtained and used to search for phages. Five phages specific to Paenibacillus were isolated and characterized (ultrastructure, morphology, biological properties, storage stability, and genome sequence). The characteristics were performed to obtain knowledge of their lytic potential and compose the final phage cocktail with high antibacterial potential and intended use of future field application. Preliminary safety studies have also been carried out on healthy bees, which suggest that the phage preparation administered is harmless.

The potential dual use of online pharmacies.

The technological advances of the 20th century resulted in the creation of the Internet and its introduction into everyday life on a global scale. The Internet provides access to information and the sale and purchase of goods. Medications are also subject to trade. Their sale is conducted by online pharmacies and their global turnover amounts to hundreds of billions of dollars. Medications ordered over the Internet are sent by mail all over the world. Considering the events of recent years, we cannot exclude the risk of a terrorist attack through online pharmacies. Terrorists can establish such companies, legally or illegally, or acquire ones already existing. Parcels, which are highly trusted by the customers of online pharmacies, can, for example, be contaminated with dangerous materials. The sale of online medications in the international system is potentially dangerous and requires international regulation.

Eight Days of Water-Only Fasting Promotes Favorable Changes in the Functioning of the Urogenital System of Middle-Aged Healthy Men.

The aim of this study was to determine whether, after 8 days of water-only fasting, there are changes in the efficiency of the lower urinary tract, the concentration of sex hormones, and the symptoms of prostate diseases in a group of middle-aged men (n = 14). For this purpose, before and after 8 days of water-only fasting (subjects drank ad libitum moderately mineralized water), and the following somatic and blood concentration measurements were made: total prostate specific antigen (PSA-T), free prostate specific antigen (PSA-F), follicle stimulating hormone (FSH), luteotropic hormone (LH), prolactin (Pr), total testosterone (T-T), free testosterone (T-F), dehydroepiandrosterone (DHEA), sex hormone globulin binding (SHGB), total cholesterol (Ch-T), ß-hydroxybutyrate (ß-HB). In addition, prostate volume (PV), volume of each testis (TV), total volume of both testes (TTV), maximal urinary flow rate (Qmax), and International Prostate Symptom Score (IPSS) values were determined. The results showed that after 8 days of water-only fasting, Qmax and IPSS improved but PV and TTV decreased significantly. There was also a decrease in blood levels of PSA-T, FSH, P, T-T, T-F, and DHEA, but SHGB concentration increased significantly. These results indicate that 8 days of water-only fasting improved lower urinary tract functions without negative health effects.

Three-Year Chronic Consumption of Low-Carbohydrate Diet Impairs Exercise Performance and Has a Small Unfavorable Effect on Lipid Profile in Middle-Aged Men.

The objective of this research was to determine whether chronic (average 3.58 ± 1.56 years) deliberate adherence to low carbohydrate diets (LCDs) is associated with selected markers of metabolism, risk factors of cardiovascular disease (CVD), body mass and physical performance in apparently healthy middle-aged men (n = 12). The control group comprised age, body mass and height matched men using mixed diets (MDs). The diets used were registered for 7 days and analyzed in terms of the energy, carbohydrate, fat and protein contents. It was found that the diets used were isoenergetic, yet varied considerably in carbohydrate and fat content. The LCDs significantly intensified the ketogenesis process, increased resting blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and heart rate, (HR) and decreased respiratory exchange ratio (RER) in relation to MD subjects. An exercise trial revealed significant impairment of exercise in subjects following the LCDs. The results showed that in the case where the subjects of two investigated groups did not differ in their somatic variables, long-term adherence to the LCDs was associated with substantially reduced exercise performance in apparently healthy subjects, along with an association with a small unfavorable effect on their lipid profile.

Phage Therapy: What Have We Learned?

In this article we explain how current events in the field of phage therapy may positively influence its future development. We discuss the shift in position of the authorities, academia, media, non-governmental organizations, regulatory agencies, patients, and doctors which could enable further advances in the research and application of the therapy. In addition, we discuss methods to obtain optimal phage preparations and suggest the potential of novel applications of phage therapy extending beyond its anti-bacterial action.

Phage Therapy in Prostatitis: Recent Prospects.

Prostatitis has various etiology including bacterial infection and dysregulated immunity; some of its forms remain a serious therapeutic challenge. Inflammation occurs in all forms of this disorder and is proposed to predispose to the development of prostate cancer (PC). There are reports that phage therapy is effective in chronic bacterial prostatitis. Recent findings suggest that phages not only eliminate bacteria, but also mediate immunomodulating (for example, anti-inflammatory) functions. The immunomodulating effects of phages could be beneficial in treating all forms of prostatitis and play some role in the prevention of the development of PC. As the etiological factors contributing to the majority of prostatitis cases remains largely unknown, and management options are often likewise limited, phage therapy merits further research as an attractive therapeutic option given its immunomodulating effects irrespective of the underlying causative factor(s).

Prospects of Phage Application in the Treatment of Acne Caused by Propionibacterium acnes.

Propionibacterium acnes is associated with purulent skin infections, and it poses a global problem for both patients and doctors. Acne vulgaris (acne) remains a problem due to its chronic character and difficulty of treatment, as well as its large impact on patients' quality of life. Due to the chronic course of the disease, treatment is long lasting, and often ineffective. Currently there are data regarding isolation of P. acnes phages, and there have been numerous studies on phage killing of P. acnes, but no data are available on phage application specifically in acne treatment. In this review, we have summarized the current knowledge on the phages active against P. acnes described so far and their potential application in the treatment of acne associated with P. acnes. The treatment of acne with phages may be important in order to reduce the overuse of antibiotics, which are currently the main acne treatment. However, more detailed studies are first needed to understand phage functioning in the skin microbiome and the possibility to use phages to combat P. acnes.

Antiphage activity of sera during phage therapy in relation to its outcome.

AIM: The aim was to study the association between the phage neutralization of patients' sera and the clinical outcome of phage therapy (PT). PATIENTS: About 62 patients with various bacterial infections receiving PT as well as 30 healthy volunteers were studied. MATERIALS & METHODS: Antiphage activity of sera (AAS) was examined using the phage neutralization test of different types of phages before and during PT in relation to the route of phage administration and correlated with the results of PT. RESULTS & CONCLUSION: The analysis of the association between AAS level and clinical results indicated that the level of AAS is not correlated with the outcome of PT.

Phage Therapy: Combating Infections with Potential for Evolving from Merely a Treatment for Complications to Targeting Diseases.

Antimicrobial resistance is considered to be one of the greatest challenges of medicine and our civilization. Lack of progress in developing new anti-bacterial agents has greatly revived interest in using phage therapy to combat antibiotic-resistant infections. Although a number of clinical trials are underway and more are planned, the realistic perspective of registration of phage preparations and their entering the health market and significantly contributing to the current antimicrobial crisis is rather remote. Therefore, in addition to planning further clinical trials, our present approach of phage treatment carried out as experimental therapy (compassionate use) should be expanded to address the growing and urgent needs of increasing cohorts of patients for whom no alternative treatment is currently available. During the past 11 years of our phage therapy center's operation, we have obtained relevant clinical and laboratory data which not only confirm the safety of the therapy but also provide important information shedding more light on many aspects of the therapy, contributing to its optimization and allowing for construction of the most appropriate clinical trials. New data on phage biology and interactions with the immune system suggest that in the future phage therapy may evolve from dealing with complications to targeting diseases. However, further studies are necessary to confirm this promising trend.

The Effect of Bacteriophage Preparations on Intracellular Killing of Bacteria by Phagocytes.

Intracellular killing of bacteria is one of the fundamental mechanisms against invading pathogens. Impaired intracellular killing of bacteria by phagocytes may be the reason of chronic infections and may be caused by antibiotics or substances that can be produced by some bacteria. Therefore, it was of great practical importance to examine whether phage preparations may influence the process of phagocyte intracellular killing of bacteria. It may be important especially in the case of patients qualified for experimental phage therapy (approximately half of the patients with chronic bacterial infections have their immunity impaired). Our analysis included 51 patients with chronic Gram-negative and Gram-positive bacterial infections treated with phage preparations at the Phage Therapy Unit in Wroclaw. The aim of the study was to investigate the effect of experimental phage therapy on intracellular killing of bacteria by patients' peripheral blood monocytes and polymorphonuclear neutrophils. We observed that phage therapy does not reduce patients' phagocytes' ability to kill bacteria, and it does not affect the activity of phagocytes in patients with initially reduced ability to kill bacteria intracellularly. Our results suggest that experimental phage therapy has no significant adverse effects on the bactericidal properties of phagocytes, which confirms the safety of the therapy.