Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann-Pick disease type C treatment.

BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear. METHODS: We estimated CD-UC complexation for nine CD derivatives derived from native α-, ß-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models. FINDINGS: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability. CONCLUSIONS: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC.

Comparison of the clinical and pathological characteristics of ultrasound-guided biopsy for breast masses and non-mass lesions between 16-gauge spring-loaded core needle biopsy and 12-gauge spring-loaded vacuum-assisted biopsy.

PURPOSE: To retrospectively compare the clinical and pathological characteristics of breast masses and non-mass lesions that underwent ultrasound (US)-guided 16-gauge spring-loaded core needle biopsy (CNB) or 12-gauge spring-loaded vacuum-assisted biopsy (VAB). METHODS: We retrospectively compared the results from US-guided diagnostic breast biopsy performed with a 16-gauge CNB (Magnum™) or a 12-gauge VAB (Celero®). The patients' backgrounds and pathological features for each device were examined. RESULTS: In 453 patients with 500 lesions, 373 lesions underwent CNB and 127 underwent VAB. The positive biopsy rate (positive predictive value 3) was significantly higher for VAB (92/127; 72.4%) than for CNB (231/373; 61.9%) (P = 0.032). Non-mass lesions were biopsied more frequently with VAB (57/127; 47.4%) than with CNB (27/378; 7.14%) (P = 0.000). The upgrade rate from high-risk to malignant lesions was significantly higher for CNB (5/19; 26.3%) than for VAB (1/8; 12.5%) (P = 0.043). There were five (1.34%) specimen failures with CNB and one (0.78%) with VAB, 18 (4.82%) re-biopsies with CNB and three (2.36%) with VAB, and 11/21 (52.4%) upgrades from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) with CNB and 11/30 (36.7%) with VAB. Although these rates tended to be higher with CNB than with VAB, the difference was not significant. CONCLUSION: Although VAB had a significantly higher rate of non-mass lesion biopsies, the upgrade rate from high-risk to malignant lesions was significantly lower for VAB than for CNB. US-guided 12-gauge spring-loaded VAB may be more appropriate for biopsy of non-mass lesions.

Modification of the immune response by bacteriophages alters methicillin-resistant Staphylococcus aureus infection.

There is an urgent need to develop phage therapies for multidrug-resistant bacterial infections. However, although bacteria have been shown to be susceptible to phage therapy, phage therapy is not sufficient in some cases. PhiMR003 is a methicillin-resistant Staphylococcus aureus phage previously isolated from sewage influent, and it has demonstrated high lytic activity and a broad host range to MRSA clinical isolates in vitro. To investigate the potential of phiMR003 for the treatment of MRSA infection, the effects of phiMR003 on immune responses in vivo were analysed using phiMR003-susceptible MRSA strains in a mouse wound infection model. Additionally, we assessed whether phiMR003 could affect the immune response to infection with a nonsusceptible MRSA strain. Interestingly, wounds infected with both susceptible and nonsusceptible MRSA strains treated with phiMR003 demonstrated decreased bacterial load, reduced inflammation and accelerated wound closure. Moreover, the infiltration of inflammatory cells in infected tissue was altered by phiMR003. While the effects of phiMR003 on inflammation and bacterial load disappeared with heat inactivation of phiMR003. Transcripts of proinflammatory cytokines induced by lipopolysaccharide were reduced in mouse peritoneal macrophages. These results show that the immune modulation occurring as a response to the phage itself improves the clinical outcomes of phage therapy.

Clinical characteristics of patients with pneumatosis intestinalis.

BACKGROUND: Several theories explaining the development of pneumatosis intestinalis (PI) have been reported, but a substantial portion of cases have been idiopathic. Additionally, predictors of bowel ischaemia in PI have not been fully investigated, while PI with bowel ischaemia has deteriorated overall outcomes of PI. METHODS: Sixty-four patients diagnosed with PI (2009-2019) were allocated to two groups: with (group 1; n = 15 (23%)) and without (group 2; n = 49 (77%)) bowel ischaemia. Fourteen patients underwent emergency surgery, and bowel ischaemia was identified in nine (64%). Six patients in group 1 were diagnosed with bowel ischaemia, and were treated palliatively. On medical charts, we determined underlying conditions of PI, compared the characteristics and outcomes between the groups, and identified the predictors of bowel ischaemia. RESULTS: Group 1 patients more commonly showed abdominal pain, lower base excess, higher C-reactive protein concentrations, higher white blood cell counts and higher neutrophil-to-lymphocyte ratios, and more frequent comorbid ascites, free air and hepatic portal vein gas. Of nine bowel ischaemia surgery patients, three (33%) died; all because of anastomotic leak. All except three patients in group 2, who presented with aspiration pneumonia, responded to treatment. Only one patient had an unknown cause (1/64, 1.6%), and various underlying conditions in secondary PI were confirmed. CONCLUSION: Idiopathic PI may be identified rarely using current imaging and knowledge, but outcomes in PI patients with bowel ischaemia remain unsatisfactory. Earlier identification of bowel ischaemia by various specialists in accordance with predictors of bowel ischaemia could improve overall outcomes in PI patients.

Clinical features of patients with hepatic portal venous gas.

BACKGROUND: Hepatic portal venous gas (HPVG) is a rare clinical condition that is caused by a variety of underlying diseases. However, the factors that would permit accurate identification of bowel ischemia, requiring surgery, in patients with HPVG have not been fully investigated. METHODS: Thirty patients that had been diagnosed with HPVG using computed tomography between 2010 and 2019 were allocated to two groups on the basis of clinical and intraoperative findings: those with (Group 1; n = 12 [40%]) and without (Group 2; n = 18 [60%]) bowel ischemia. Eleven patients underwent emergency surgery, and bowel ischemia was identified in eight of these (73%). Four patients in Group 1 were diagnosed with bowel ischemia, but treated palliatively because of their general condition. We compared the characteristics and outcomes of Groups 1 and 2 and identified possible prognostic factors for bowel ischemia. RESULTS: At admission, patients in Group 1 more commonly showed the peritoneal irritation sign, had lower base excess, higher lactate, and higher C-reactive protein, and more frequently had comorbid intestinal pneumatosis. Of the eight bowel ischemia surgery patients, four (50%) died, mainly because of anastomotic leak following bowel resection and primary anastomosis (3/4, 75%). All except one patient in Group 2, who presented with aspiration pneumonia, responded better to treatment. CONCLUSIONS: Earlier identification and grading of bowel ischemia according to the findings at admission should benefit patients with HPVG by reducing the incidence of unnecessary surgery and increasing the use of safer procedures, such as prophylactic stoma placement.

[Surgical removal of choroidal neovascularization in angioid streaks].

PURPOSE: All the studies so far on surgical removal of choroidal neovascularization (CNV) in angioid streaks(AS) were conducted on a small number of cases. Therefore, a definitive evaluation of the surgical method was not available. The present study aimed to evaluate this surgical modality. SUBJECTS AND METHOD: We performed surgical removal of foveal CNV accompanied by AS. Eighteen eyes of seventeen patients were available for follow-up of over 12 months. Surgical indications included foveal CNV, fluorescence leakage from the CNV in late-phase fluorescein angiography, and visual acuity of 0.3 or lower. RESULTS: The best visual acuity was improved in 44% and unchanged in 44%. The final visual acuity was improved in 33% and unchanged in 39%. 22% had a preoperative visual acuity of 0.2 or above; and 44% and 17% achieved best and final visual acuity, respectively, of 0.2 or above. Since all cases developed atrophy of the choriocapillaris in the fovea, none of the cases were capable of fixation within atrophy. The fixation point was localized outside atrophy in 56% and fixation was poor in 44%. The diameter of postoperative atrophy of choriocapillaris was significantly greater (p < 0.05) than the preoperative CNV diameter. CNV recurred in 8 eyes(44%), 88% of which occurred within one year. CONCLUSION: Surgical removal of CNV in AS is an effective method to maintain preoperative visual acuity.