University Hospital Kyoto Prefectural University of Medicine

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Haemophagocytic lymphohistiocytosis (HLH) may cause meningoencephalitis and significant neurological sequelae. We examined the relationship between neurological symptoms and cerebrospinal fluid (CSF) at diagnosis, and long-term outcome, in all children enroled in the HLH-94-study prior to July 1, 2003, for whom information on CSF at diagnosis was available (n = 193). Patients were divided into four groups: (i) normal CSF (cells/protein) and no neurological symptoms (n = 71); (ii) normal CSF but neurological symptoms (n = 21); (iii) abnormal CSF but no symptoms (n = 50); and (iv) abnormal CSF with neurological symptoms (n = 51). At diagnosis, neurological symptoms were reported in 72/193 (37%) (seizures = 23); abnormal CSF in 101/193 (52%), and either or both in 122/193 (63%). Altogether 16/107 (15%) survivors had neurological sequelae at follow-up (median 5.3 years). Multivariate hazard ratios (HR) for mortality were 0.98 [95% confidence interval (CI) = 0.42-2.31], 1.52 (0.82-2.82) and 2.05 (1.13-3.72) for groups 2-4, compared with group 1. Moreover, sequelae were more frequent in group 4 (7/21, 33%) compared to groups 1-3 (9/86, 10%) (P = 0.015). Patients with abnormal CSF at diagnosis had significantly increased mortality [HR = 1.78 (95% CI = 1.08-2.92), P = 0.023]. Thus, a substantial proportion of HLH survivors suffer neurological sequelae, and children with abnormal CSF have increased risk of mortality and neurological sequelae. Prompt treatment of HLH at onset or relapse may reduce these complications.

There have been many reports on the roles of intestinal flora and intestinal environment in health promotion and disease prevention. Beneficial bacteria such as Bifidobacterium and lactic acid-producing bacteria have been shown to improve the intestinal environment, and yield a good effect on metabolism, immunity and nerve response. In this review, in addition to these beneficial bacteria, we introduced Akkermansia muciniphila as a next-generation beneficial microbe. Several reports indicate that Akkermansia muciniphila affects glucose metabolism, lipid metabolism, and intestinal immunity, and that certain food ingredients such as polyphenols may increase the abundance of Akkermansia muciniphila in the gut.

PURPOSE: The study was performed to clarify in the hemophagocytic syndrome (HPS) how cytokinemia plays a role in its pathogenesis and if cytokinemia is of prognostic value. PATIENTS AND METHODS: Serum concentrations of ferritin, interferon (IFN)-gamma, soluble interleukin-2 (IL-2) receptor, IL-6, and other cytokines were determined during the acute phase of the HPS in 29 children and three adults. Data comparing malignancy-associated (MAHS; n = 17) and infection-associated hemophagocytic syndrome (IAHS; n = 15) and those comparing surviving and fatal cases were assessed. RESULTS: Hyperferritinemia and hypercytokinemia were present in all patients with HPS. Eleven of the 17 MAHS and three of the 15 IAHS cases were fatal (p < 0.05). No significant difference in cytokine concentrations was observed between MAHS and IAHS. CONCLUSIONS: In terms of cytokine effect on patient outcome, serum concentrations of IL-6 > 300 ng/L and IFN-gamma concentrations > 30 U/ml or soluble IL-2 receptor (sIL-2R) concentrations > 10,000 U/ml were considered to reflect a poor prognosis in HPS patients.

Haemophagocytic lymphohistiocytosis (HLH) poses major therapeutic challenges, and the primary inherited form, familial haemophagocytic lymphohistiocytosis (FHL), is usually fatal. We evaluated, including Cox regression analysis, survival in 86 children (29 familial) that received HLH-94-therapy (etoposide, dexamethasone, ciclosporin) followed by allogeneic stem cell transplantation (SCT) between 1995 and 2000. The overall estimated 3-year-survival post-SCT was 64% [confidence interval (CI) = +/-10%] (n = 86); 71 +/- 18% in those patients with a matched related donor (MRD, n = 24), 70 +/- 16% with a matched unrelated donor (MUD, n = 33), 50 +/- 24% with a family haploidentical donor (haploidentical, n = 16), and 54 +/- 27% with a mismatched unrelated donor (MMUD, n = 13). After adjustment for potential confounding factors, estimated odds ratios (OR) for mortality were 1.93 (CI =0.61-6.19) for MUD, 3.31 (1.02-10.76) for haploidentical, and 3.01 (0.91-9.97) for MMUD, compared with MRD. In children with active disease after 2-months of therapy (n = 43) the OR was 2.75 (1.26-5.99), compared with inactive disease (n = 43). In children with active disease at SCT (n = 37), the OR was 1.80 (0.80-4.06) compared with inactive disease (n = 49), after adjustment for disease activity at 2-months. Mortality was predominantly transplant-related. Most HLH patients survived SCT using MRD or MUD, and survival with partially mismatched donors was also acceptable. Patients that responded well to initial pretransplant-induction therapy fared best, but some persisting HLH activity should not automatically preclude performing SCT.

The familial form of hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder. Although the prognosis for Epstein-Barr virus-associated HLH (EBV-HLH) remains uncertain, numerous reports indicate that it can also be fatal in a substantial proportion of cases. We therefore assessed the potential of immunochemotherapy with a core combination of steroids and etoposide to control EBV-HLH in 17 infants and children who met stringent diagnostic criteria for this reactive disorder of the mononuclear phagocyte system. Treatment of life-threatening emergencies was left to the discretion of participating investigators and typically included either intravenous Ig or cyclosporin A (CSA). Five patients (29%) entered complete remission during the induction phase (1 to 2 months), whereas 10 others (57%) required additional treatment to achieve this status. In 2 cases, immunochemotherapy was ineffective, prompting allogeneic bone marrow transplantation. Severe but reversible myelosuppression was a common finding; adverse late sequelae were limited to epileptic activity in one child and chronic EBV infection in 2 others. Fourteen of the 17 patients treated with immunochemotherapy have maintained their complete responses for 4+ to 39+ months (median, 15+ months), suggesting a low probability of disease recurrence. These results provide a new perspective on EBV-HLH, showing effective control (and perhaps cure) of the majority of EBV-HLH cases without bone marrow transplantation, using steroids and etoposide, with or without immunomodulatory agents.

BACKGROUND: The prevalence and clinical characteristics of osteochondritis dissecans (OCD) of the humeral capitellum among adolescent baseball players are unknown. PURPOSE: To determine the OCD prevalence in adolescent competitive baseball players and to investigate the clinical characteristics of these patients. STUDY DESIGN: Cross-sectional and case-control study; Level of evidence, 3. METHODS: A total of 2433 baseball players (mean age, 14.5 ± 1.5 years) belonging to junior high school and high school baseball clubs were enrolled. Players completed a questionnaire, and the elbow of each player's throwing arm was assessed by ultrasonography. Participants with abnormal results on ultrasonography were further examined through radiographic study. The OCD lesions were classified into stages based on radiographic results, and demographic data were compared between players with and without OCD lesions. RESULTS: Osteochondritis dissecans of the humeral capitellum was found in 82 (3.4%) elbows by ultrasonography. Players with an OCD lesion began playing baseball at an earlier age (P = .016), had a longer duration of competitive play (P = .0013), and had experienced more present (P = .0025) and past (P < .0001) elbow pain compared with players without a lesion. There were no differences between the 2 groups in the position played (P = .26). Sixty-eight patients underwent further radiographic examination for OCD (radiography, computed tomography, magnetic resonance imaging). Of these players, 10 (14.7%) were classified as having stage I OCD (radiolucent stage); 26 (38.2%), stage II (fragmentation stage); 9 (13.2%), stage III (loose body stage); 9 (13.2%), stage IV (residual stage); and 14 (23.5%), stage V (postoperative stage). CONCLUSION: The prevalence of OCD of the humeral capitellum, including latent cases, was 3.4% among adolescent baseball players. Players with OCD lesions began playing baseball at earlier ages, had played for longer periods, and had experienced more elbow pain. The player's current baseball position may not be related to the existence of OCD lesions in adolescents.

The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macrophages. Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a strong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein-Barr virus (EBV)-associated immunodeficiency resulting from defects in SH2D1A, a small SH2 domain-containing protein expressed in T lymphocytes and natural killer cells. Here it is shown that 4 of 25 male patients with HLH who were examined harbored germline SH2D1A mutations. Among these 4 patients, only 2 had family histories consistent with XLP. On the basis of these findings, it is suggested that all male patients with EBV-associated hemophagocytosis be screened for mutations in SH2D1A. Patients identified as having XLP should undergo genetic counseling, and be followed long-term for development of lymphoma and hypogammaglobulinemia.

OBJECTIVE: To assess the effects of plasma exchange on important outcomes in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). DESIGN: Systematic review and meta-analysis of randomised controlled trials. ELIGIBILITY CRITERIA: Randomised controlled trials investigating effects of plasma exchange in patients with AAV or pauci-immune rapidly progressive glomerulonephritis and at least 12 months' follow-up. INFORMATION SOURCES: Prior systematic reviews, updated by searching Medline, Embase, and CENTRAL to July 2020. RISK OF BIAS: Reviewers independently identified studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. SYNTHESIS OF RESULTS: Meta-analyses were conducted using random effects models to calculate risk ratios and 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methods. Outcomes were assessed after at least12 months of follow-up and included all-cause mortality, end stage kidney disease (ESKD), serious infections, disease relapse, serious adverse events, and quality of life. RESULTS: Nine trials including 1060 participants met eligibility criteria. There were no important effects of plasma exchange on all-cause mortality (relative risk 0.90 (95% CI 0.64 to 1.27), moderate certainty). Data from seven trials including 999 participants that reported ESKD demonstrated that plasma exchange reduced the risk of ESKD at 12 months (relative risk 0.62 (0.39 to 0.98), moderate certainty) with no evidence of subgroup effects. Data from four trials including 908 participants showed that plasma exchange increased the risk of serious infections at 12 months (relative risk 1.27 (1.08 to 1.49), moderate certainty). The effects of plasma exchange on other outcomes were uncertain or considered unimportant to patients. LIMITATIONS OF EVIDENCE: There is a relative sparsity of events, and treatment effect estimates are therefore imprecise. Subgroup effects at the participant level could not be evaluated. INTERPRETATION: For the treatment of AAV, plasma exchange has no important effect on mortality, reduces the 12 month risk of ESKD, but increases the risk of serious infections. FUNDING: No funding was received. REGISTRATION: This is an update of a previously unregistered systematic review and meta-analysis published in 2014.

RATIONALE: Proinflammatory cytokines play an important role in ventilator-induced lung injury (VILI). High-mobility group box-1 (HMGB1) is a macrophage-derived proinflammatory cytokine that can cause lung injury. OBJECTIVES: This study tested the hypothesis that HMGB1 is released in intact lungs ventilated with large Vt. A second objective was to identify the source of HMGB1. A third objective was to examine the effects of blocking HMGB1 on the subsequent development of VILI. METHODS: Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained from rabbits mechanically ventilated for 4 h with a small (8 ml/kg) versus a large (30 ml/kg) Vt. BALF was also obtained from rabbits with intratracheal instillation of anti-HMGB1 antibody before the initiation of large Vt ventilation. MEASUREMENTS AND MAIN RESULTS: The concentrations of HMGB1 in BALF were fivefold higher in the large than in the small Vt group. Immunohistochemistry and immunofluorescence studies revealed expression of HMGB1 in the cytoplasm of macrophages and neutrophils in lungs ventilated with large Vt. Blocking HMGB1 improved oxygenation, limited microvascular permeability and neutrophil influx into the alveolar lumen, and decreased concentrations of tumor necrosis factor-alpha in BALF. CONCLUSIONS: These observations suggest that HMGB1 could be one of the deteriorating factors in the development of VILI.

Of 37 patients with congenital choledochal dilatation, aged 8 days to 12 years, who had undergone excision with Roux-en-Y hepaticojejunostomy, 26 patients could be analyzed for morphologic abnormalities and pathophysiology of the biliary tract. Of the 26 patients with congenital choledochal dilatation, 25 (96.2%) had an abnormal choledochopancreaticoductal junction. Of the 12 patients with cystic-type choledochal dilatation, 10 had the C-P type of abnormal choledochopancreaticoductal junction, and of the 13 patients with fusiform-type choledochal dilatation, nine had the P-C type. The amylase levels in the choledochal cyst and the gallbladder were elevated regardless of the form of choledochal dilatation. An adenocarcinoma in a cystic choledochal dilatation was found in one child. Therefore, longstanding inflammation of the biliary tract caused by the reflux of pancreatic juice might be one of the factors in carcinogenesis in the biliary tract. This free reflux of pancreatic juice was demonstrated not only by amylase levels in the biliary tract but also by intraoperative biliary manometry. This reflux might be explained by the lack of sphincter function at the junction of the common bile and pancreatic ducts.

Serum ferritin level was measured serially in three malignant histiocytosis (MH) and five virus-associated hemophagocytic syndrome (VAHS) patients. Serum ferritin levels were greater than 1000 ng/ml at the early phase of disease. When disseminated intravascular coagulation (DIC) developed in patients, serum ferritin levels elevated further to greater than 12,000 ng/ml. MH patients were treated by combination chemotherapy, and VAHS patients were given prednisone. Each MH and VAHS patient died within 1 week from the onset of DIC, without decrease of serum ferritin level. One MH patient with continued high serum ferritin levels for 3 months after DIC also died. The remaining patients with decreased serum ferritin values less than 1000 ng/ml at 3 months after DIC are now alive with normal serum ferritin levels. These results suggest that serum ferritin level in histiocytic proliferative disorders is a useful indicator of disease activity in both neoplastic and reactive conditions rather than only a marker of malignant process.

BACKGROUND: Observational registries comparing coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) have reported long-term survival results that are discordant with those of randomized trials. METHODS AND RESULTS: We conducted a multicenter study in Japan enrolling consecutive patients undergoing first CABG or PCI between January 2000 and December 2002. Among 9877 patients enrolled, 5420 (PCI: 3712, CABG: 1708) had multivessel disease without left main involvement. Because age is an important determinant when choosing revascularization strategies, survival analysis was stratified by either age >/=75 or <75 years. Analyses were also performed in other relevant subgroups. Median follow-up interval was 1284 days with 95% follow-up rate at 2 years. At 3 years, unadjusted survival rates were 91.7% and 89.6% in the CABG and PCI groups, respectively (log rank P=0.26). After adjustment for baseline characteristics, survival outcome tended to be better after CABG (hazard ratio for death after PCI versus CABG [HR], 95% confidence interval [CI]: 1.23 [0.99-1.53], P=0.06). Adjusted survival outcomes also tended to be better for CABG among elderly patients (HR [95%CI]: 1.37 [0.98-1.92] P=0.07), but not among nonelderly patients (HR [95% CI]: 1.09 [0.82-1.46], P=0.55). Unadjusted and adjusted survival outcome for CABG and PCI were not significantly different in any subgroups when elderly patients were excluded from analysis. CONCLUSIONS: In the CREDO-Kyoto registry, survival outcomes among patients <75 years of age were similar after PCI and CABG, a result that is consistent with those of randomized trials.

BACKGROUND: Ultrasound-guided central venous catheterization has been recommended to increase the procedural success rate and enhance patient safety. However, few studies have examined the potential advantages of one ultrasound technique with another, specifically in small infants. METHODS: The authors randomly assigned 60 neonates and infants weighing less than 7.5 kg to an ultrasound-guided skin-marking method (n = 27) versus real-time ultrasound-assisted internal jugular venous catheterization (n = 33). The times to successful puncture of the internal jugular vein and to catheterization were measured. Attempts at needle punctures for successful catheterization were counted. Procedural complications were recorded. RESULTS: In the real-time group, compared with the skin- marking group, venous puncture was completed faster (P = 0.03), the time required to catheterize was shorter (P < 0.01), and fewer needle passes were needed. Specifically, fewer than three attempts at puncture were made in 100% of patients in the real-time group, versus 74% of patients in the skin-marking group (P < 0.01). A hematoma and an arterial puncture occurred in one patient each in the skin-marking group. CONCLUSIONS: The real-time ultrasound guidance method could enhance procedural efficacy and safety of internal jugular catheterization in neonates and infants.

PURPOSE: In severe ocular surface diseases, pathologic keratinization of the ordinarily nonkeratinized corneal and conjunctival mucosal epithelia results in severe visual loss. The expression in conjunctivalized corneas of various proteins known to play important roles in the physiological keratinization process in human epidermis was examined to better understand the mechanism of keratinization. METHODS: Conjunctiva covering the cornea was examined in 12 eyes with ocular surface disease in the chronic cicatricial phase. These comprised four Stevens-Johnson syndrome, four ocular cicatricial pemphigoid, and four chemical injuries. Normal conjunctivas from four age-matched individuals served as controls. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to investigate transglutaminase 1 gene expression and immunohistochemistry to study the expression of transglutaminase 1 protein along with other keratinization-related proteins (involucrin, loricrin, filaggrin, and cytokeratins 1 and 10) and cytokeratin pairs 4/13 and 3/12. RESULTS: Semiquantitative RT-PCR showed that transglutaminase 1 mRNA expression was upregulated in keratinized conjunctiva compared with normal. Also, in this tissue, immunohistochemistry demonstrated elevated levels of transglutaminase 1, involucrin, filaggrin, and the cytokeratin pair 1/10. Levels of loricrin and cytokeratin pairs 4/13 and 3/12, however, remained the same. CONCLUSIONS: Various keratinization-related proteins, transglutaminase 1 included, are most likely involved in the pathogenesis of cicatrizing ocular surface diseases.

We carried out a multicenter dose-escalation phase I study of oral OPB-51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory hematological malignancies to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB-51602 at doses of 1, 2, 3, 4, and 6 mg in the "3 + 3" dose escalation design. The most common treatment-related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug-related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose-limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1-2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB-51602 was rapidly absorbed, and exposure tended to increase in a dose-dependent manner. Accumulation of OPB-51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB-51602 was 6 mg. OPB-51602 was safe and well tolerated in a dose range of 1-4 mg. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB-51602 for hematological malignancies with a daily dosing schedule was terminated.

To clarify the correlation between Epstein-Barr virus (EBV) involvement and hypercytokinaemia in haemophagocytic lymphohistiocytosis (HLH), we analysed serum interferon-gamma levels and EBV-DNA in biological specimens obtained from 25 HLH cases (23 children and two adults). We found that HLH patients showed a wide range of serum IFN-gamma levels from 0.2 to 1300 U/ml, with a median 126 U/ml for EBV-DNA-positive (n = 9) and 4.5 U/ml for EBV-DNA-negative (n = 16) groups. The latter group could be classified further into a group with hyper-IFN-gamma-naemia (> 4.5 U/ml) (n = 8) and a group without hyper-IFN-gamma-naemia (n = 8). The survival of the hyper-IFN-gamma-naemic cases was significantly poorer than non-hyper-IFN-gamma-naemic cases. We conclude that EBV is probably involved in one third of the HLH cases, all of whom show hyper-IFN-gamma-naemia, and in the half of the HLH cases with hyper-IFN-gamma-naemia who have a rapidly fatal outcome.

BACKGROUND AND PURPOSE: A long-term follow-up study was conducted in patients with lacunar infarct to assess how 24-hour blood pressure monitoring values and MRI findings, in particular lacunar infarcts and diffuse white matter lesions, can predict subsequent development of dementia and vascular events, which include cerebrovascular and cardiovascular events. METHODS: One hundred seventy-seven patients were tracked for a mean of 8.9 years of follow-up. Documented events comprise the development of dementia and the occurrence of vascular events. The predictors for developing dementia and vascular events were separately evaluated by Cox proportional hazards analysis. RESULTS: Twenty-six patients developed dementia (0.17/100 patient-years). Male sex (relative risk [RR], 4.2; 95% CI, 1.2 to 14.7), cognitive impairment (RR, 3.0; 95% CI, 1.0 to 8.5), confluent DWML (moderate: RR, 7.1; 95% CI, 1.6 to 31.5; severe: RR, 35.8; 95% CI, 7.2 to 177.3), and nondipping status (RR, 7.1; 95% CI, 2.2 to 22.0) were independent predictors for dementia. Forty-six patients suffered from vascular events (3.11/100 patient-years). Diabetes mellitus (RR, 5.7; 95% CI, 2.7 to 11.9), multiple lacunae (moderate: RR, 6.4; 95% CI, 2.5 to 15.8; severe: RR, 8.5; 95% CI, 3.1 to 23.3), and high 24-hour systolic blood pressure (>145 mm Hg versus <130 mm Hg) (RR, 10.3; 95% CI, 1.3 to 81.3) were independent predictors for vascular events. CONCLUSIONS: Predictors for developing dementia and vascular events appear to differ. Male sex, confluent diffuse white matter lesions, and nondipping status were independent predictors for subsequent development of dementia, while diabetes mellitus, multiple lacunae, and high 24-hour systolic blood pressure were independent predictors for vascular events.

The increase in the incidence of antibiotic-resistant bacteria poses a global public health threat. According to a 2019 WHO report, approximately 1.27 million deaths were attributed to antibiotic-resistant bacteria, with many cases linked to specific bacterial species, such as drug-resistant Pseudomonas aeruginosa and Staphylococcus aureus. By 2050, the number of deaths caused by these bacteria is predicted to surpass that caused by cancer. In response to this serious situation, phage therapy, an alternative to antibiotic treatment, has gained attention. Phage therapy involves the use of viruses that target specific bacteria to treat infections. This method has proven effective in multiple clinical cases, particularly for patients with severe infections caused by multidrug-resistant bacteria. For example, there are reports of patients with systemic infections caused by multidrug-resistant Acinetobacter who recovered following phage administration and patients infected with panresistant Pseudomonas aeruginosa who were cured by phage therapy. A key feature of phage therapy is its high specificity. Phages infect only specific bacteria and eliminate them. However, this specificity can also be a disadvantage, as careful selection of the appropriate phage for the target bacteria is needed. Additionally, bacteria can develop resistance to phages, potentially reducing treatment effectiveness over time. Efforts are underway to select, combine, and improve phages to address these challenges. In Belgium, a national phage bank has been established, and in the United States, the University of California, San Diego, has founded Innovative Phage Applications and Therapeutics (IPATH), marking significant progress toward the clinical application of phage therapy in the country. As a result, phage therapy is emerging as a component of personalized medicine, offering a new treatment option against antibiotic-resistant bacteria. The clinical application of phage therapy is particularly important in life-saving treatments for patients with severe bacterial infections, and its use in conjunction with antibiotics could enhance therapeutic outcomes. Continued research and development of this therapy could provide hope for many more patients in the future.

OBJECTIVE: To investigate the effects of adenovirus vector-mediated gene transduction of E. coli beta-galactosidase (LacZ), transforming growth factor-beta 1 (TGF-beta 1), and heat shock protein 70 (HSP 70) on human chondrocyte-like cell line (HCS-2/8). METHODS: We examined expression of transduced genes and their expression periods by 5 bromo-4-chloroindolyl-beta-D-galactoside (X-gal) staining. Northern blotting, ELISA, and Western blotting. To assess the influence of TGF-beta 1 and HSP70 gene transduction, the expression of mRNA of type II collagen, proteoglycan core protein, matrix metalloproteinase 3 (MMP3) and tissue inhibitor of matrix metalloproteinase 1 were examined by Northern blotting. RESULTS: Staining with X-gal indicated that the genes were transduced into a majority of the cells. Expression of the transduced genes in the cells was continued for at least 21 days. Transduction of TGF-beta 1 gene enhanced mRNA expression of type II collagen and proteoglycan core protein, but suppressed MMP3 mRNA expression in the cells. Expression of HSP70 was also high. Enhanced expression of HSP70 elevated mRNA expression of proteoglycan core protein. CONCLUSION: These results indicate adenovirus vector is useful in chondrocyte gene therapy, and it could be an efficient mediator of TGF-beta 1 and HSP70 gene transduction.