Anti-osteoporotic drug efficacy for periprosthetic bone loss after total hip arthroplasty: A systematic review and network meta-analysis.

BACKGROUND: Periprosthetic bone loss following total hip arthroplasty (THA) threatens prosthesis stability. This systematic review and network meta-analysis aimed to compare the efficacy of anti-osteoporotic drugs for measures of hip function according to functional outcomes, periprosthetic femoral bone mineral density loss in each Gruen zone, and revision surgery after THA. METHODS: The systematic search of six literature databases was conducted in December 2021 in accordance with PRISMA guidelines. Adult participants who underwent primary THA were included. A random-effects network meta-analysis was performed within a frequentist framework, and the confidence in the evidence for each outcome was evaluated using the CINeMA tool, which assessed the credibility of results from the network meta-analysis. We included 22 randomized controlled trials (1243 participants) comparing the efficacy and safety of bisphosphonates (including etidronate, clodronate, alendronate, risedronate, pamidronate, and zoledronate), denosumab, selective estrogen receptor modulator, teriparatide, calcium + vitamin D, calcium, and vitamin D. We defined the period for revision surgery as the final follow-up period. RESULTS: Raloxifene, bisphosphonate, calcium + vitamin D, and denosumab for prosthetic hip function might have minimal differences when compared with placebos. The magnitude of the anti-osteoporotic drug effect on periprosthetic femoral bone loss varied across different Gruen zones. Bisphosphonate, denosumab, teriparatide might be more effective than placebo in Gruen zone 1 at 12 months after THA. Additionally, bisphosphonate might be more effective than placebo in Gruen zones 2, 5, 6, and 7 at 12 months after THA. Denosumab was efficacious in preventing bone loss in Gruen zones 6 and 7 at 12 months after THA. Teriparatide was likely to be efficacious in preventing bone loss in Gruen zone 7 at 12 months after THA. Raloxifene was slightly efficacious in preventing bone loss in Gruen zones 2 and 3 at 12 months after THA. Calcium was slightly efficacious in preventing bone loss in Gruen zone 5 at 12 months after THA. None of the studies reported revision surgery. CONCLUSIONS: Bisphosphonate and denosumab may be effective anti-osteoporotic drugs for preventing periprosthetic proximal femoral bone loss due to stress shielding after THA, particularly in cementless proximal fixation stems, which are the most commonly used prostheses worldwide.

Histologically Proven Recurrent Synovitis after Nivolumab Treatment.

A 58-year-old woman with rheumatoid arthritis was diagnosed with methotrexate-associated Hodgkin lymphoma. After receiving several chemotherapy regimens, she started nivolumab treatment. Two weeks later, she was hospitalized with worsening finger, wrist, and elbow joint pain. A synovial biopsy of the wrist joint showed villous synovial proliferation and linear infiltration of CD68-/CD3-positive T cells (with more CD8 than CD4 T cells) but no CD20-positive B cells or CD138-positive macrophages. These findings corresponded to synovitis associated with immune-related adverse events, which are induced mainly by T cells and are different from typical rheumatoid arthritis (RA), in which B cells play a central role.

Cycloimidamicins, Novel natural lead compounds for translation inhibition in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most concerning pathogenic bacteria. We screened antibiotics using a highly drug-sensitive P. aeruginosa strain and an oligotrophic medium, and successfully isolated novel antibiotics, namely cycloimidamicins (CIMs), from a rare actinomycete strain, Lentzea sp. MM249-143F7. X-ray and nuclear magnetic resonance analyses revealed that CIMs possess a distinctive and unprecedented molecular structure, containing tetramic acid and an imidazole ring bound directly to indolone. The CIMs exhibited potent antibacterial activity against Gram-negative bacteria, as well as translation inhibition in Escherichia coli in both intact cells and in vitro. Additionally, E. coli strains resistant to known translation inhibitors did not exhibit cross-resistance to CIMs, suggesting that CIMs inhibit bacterial growth by blocking translation through a novel mechanism.

Antiplasmodial Activity Evaluation of a Bestatin-Related Aminopeptidase Inhibitor, Phebestin.

The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new therapeutic agent. From our screening, phebestin stood out with nanomolar efficacy against Plasmodium falciparum 3D7. Phebestin was initially identified as an aminopeptidase N inhibitor. Phebestin inhibited the in vitro multiplication of the P. falciparum 3D7 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains at IC50 values of 157.90 ± 6.26 nM and 268.17 ± 67.59 nM, respectively. Furthermore, phebestin exhibited no cytotoxic against human foreskin fibroblast cells at 2.5 mM. In the stage-specific assay, phebestin inhibited all parasite stages at 100 and 10-fold its IC50 concentration. Using 72-h in vitro exposure of phebestin at concentrations of 1 µM on P. falciparum 3D7 distorted the parasite morphology, showed dying signs, shrank, and prevented reinvasion of RBCs, even after the compound was washed from the culture. An in silico study found that phebestin binds to P. falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP), as observed for bestatin. In vivo evaluation using P. yoelii 17XNL-infected mice with administrations of 20 mg/kg phebestin, once daily for 7 days, resulted in significantly lower parasitemia peaks in the phebestin-treated group (19.53%) than in the untreated group (29.55%). At the same dose and treatment, P. berghei ANKA-infected mice showed reduced parasitemia levels and improved survival compared to untreated mice. These results indicate that phebestin is a promising candidate for development as a potential therapeutic agent against malaria.

Wychimicins, a new class of spirotetronate polyketides from Actinocrispum wychmicini MI503-A4.

In the course of our screening program for new anti-methicillin-resistant Staphylococcus aureus antibiotics, four novel antibiotics, termed wychimicins A-D, were isolated from the culture broth of the rare actinomycete Actinocrispum wychmicini strain MI503-AF4. Wychimicins are spirotetronates possessing a macrocyclic 13-membered ring containing trans-decalin and ß-D-xylo-hexopyranose moieties connected to C-17 by an O-glycosidic linkage according to MS, NMR and X-ray analyses. In X-ray crystal structure analysis, the Flack constant was 0.10 (11). The stereochemistry of the spirocarbon C-25 was R. Wychimicins had a minimum inhibitory concentration of 0.125-2 µg ml-1 against methicillin-resistant Staphylococcus aureus.

A Novel Grading System of Destructive Lumbar Spondyloarthropathy Based on Evaluation of the Facet Joints.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To develop and evaluate a new grading system for destructive lumbar spondyloarthropathy (DLSA) by assessing bony destruction of the facet joints; to evaluate interrater reliability; and to determine the association between anteroposterior (AP) dural sac diameter at the lumbar level and the new grading. SUMMARY OF BACKGROUND DATA: The characteristics of DLSA are unknown, hindering clinical care and research. Imaging to determine the cause of DLSA may positively contribute to patient outcome or well-being by providing prognostic information. PATIENTS AND METHODS: In the magnetic resonance images (MRIs), we measured an axial midline AP dural sac diameter and evaluated bone destruction caused by amyloidosis at the level of the center of each lumbar disk of the lumbar spine. Two orthopedic surgeons independently evaluated each case at two-month intervals and assigned the grade by rating bone destruction at each lumbar level. Weighted κ and intraclass correlation coefficients for interrater reliability were calculated. In addition, the correlation between the AP diameter of the spinal dural sac at the lumbar level and the new MRI-based DLSA grade was examined. RESULTS: The sample size of 82 patients was reached by examining records of 118 consecutive patients. The mean (SD) age of the included patients was 65 (7.2) years, and 36 (43.9%) were women. The grading of DLSA showed moderate to good interrater reliability at both assessments (κ, 0.59-0.78). Intraclass correlation coefficient showed substantial to excellent agreement (intraclass correlation coefficient, 0.63-0.86). The AP diameter of the spinal dural sac at the lumbar level showed a significant correlation with the new grading ( P <0.001). CONCLUSIONS: The new MRI-based grading system for DLSA has good interrater reliability, although the strength of agreement varies somewhat. The new grading system correlates with AP dural sac diameter. Thus, this classification focused on facet erosion, which leads to functional incompetence may be helpful in surgical decision-making.

Rediscovery of 4-Trehalosamine as a Biologically Stable, Mass-Producible, and Chemically Modifiable Trehalose Analog.

Nonreducing disaccharide trehalose is used as a stabilizer and humectant in various products and is a potential medicinal drug, showing curative effects on the animal models of various diseases. However, its use is limited as it is hydrolyzed by trehalase, a widely expressed enzyme in multiple organisms. Several trehalose analogs are prepared, including a microbial metabolite 4-trehalosamine, and their high biological stability is confirmed. For further analysis, 4-trehalosamine is selected as it shows high producibility. Compared with trehalose, 4-trehalosamine exhibits better or comparable protective activities and a high buffer capacity around the neutral pH. Another advantage of 4-trehalosamine is its chemical modifiability: simple reactions produce its various derivatives. Labeled probes and detergents are synthesized in one-pot reactions to exemplify the feasibility of their production, and their utility is confirmed for their respective applications. The labeled probes are used for mycobacterial staining. Although the derivative detergents can be effectively used in membrane protein research, long-chain detergents show 1000-3000-fold stronger autophagy-inducing activity in cultured cells than trehalose and are expected to become a drug lead and research reagent. These results indicate that 4-trehalosamine is a useful trehalose substitute for various purposes and a material to produce new useful derivative substances.

Association Between Simultaneous Bilateral Total Hip Arthroplasty Without Any Anticoagulant or Antiplatelet Therapy and Deep Venous Thrombosis: A Cohort Study.

BACKGROUND: The association of simultaneous bilateral total hip arthroplasty (THA) with postoperative deep venous thrombosis (DVT) remains controversial. The aim of the study is to determine whether simultaneous bilateral THA without chemoprophylaxis has a higher risk than unilateral THA without chemoprophylaxis. METHODS: This is a population-based retrospective cohort study of all adults who underwent primary THA without any anticoagulant or antiplatelet therapy between July 2012 and March 2021 at the Department of Orthopedic Surgery, Toranomon Hospital, Tokyo, Japan. The association of simultaneous bilateral THA with postoperative DVT was examined by unadjusted analysis and overlap propensity score weighting. The primary outcome was the incidence of DVT (confirmed by ultrasonography of the lower limb veins) within 7 days postoperatively. RESULTS: Of the 557 consecutive patients who underwent primary THA in the study period, 458 met the inclusion criteria. The mean (standard deviation) age of these patients was 67 (11.7) years, and 364 (79.5%) were women; 75 (16.4%) of the 458 patients underwent simultaneous bilateral THA, and 383 (83.6%), unilateral THA. A total of 64 patients (14.0%) developed a postoperative venous thromboembolism, all of which were a distal DVT. The overlap weighting analysis found no significant difference in the incidence of postoperative DVT complications among patients who underwent simultaneous bilateral THA and those who underwent unilateral THA (31.1 [13.6%] vs 22.9 [10.0%], respectively; risk ratio, 1.36; 95% confidence interval, 0.67 to 2.77; P = .40). CONCLUSIONS: Our findings indicate that the occurrence of DVT within 7 days after surgery is not significantly different between patients undergoing simultaneous bilateral THA or unilateral THA without any anticoagulant or antiplatelet therapy. LEVEL OF EVIDENCE: Level II-III.

Effect of loaded exercise for renal osteodystrophy.

We performed bone histomorphometric analysis of biopsy specimens from two patients with hyper- and hypoparathyroidism and a history of long-term hemodialysis (HD) because of diabetes. Case 1, a 53-year-old man with hyperparathyroidism, had been on HD for 22 years, and Case 2, a 54-year-old woman with hypoparathyroidism, for 20 years. Intact parathyroid hormone levels were 1070 and 3 pg/mL, respectively. Case 1 had mixed renal osteodystrophy (fibrous tissue volume to total volume [Fb.V/TV], 5.21%; osteoid volume to bone volume [OV/BV], 19.8%), and Case 2 had adynamic renal osteodystrophy (Fb.V/TV, 0%; OV/BV, 0.54%). Case 1 showed cortical bone thinning (cortical width, 0.2 mm) and porosis (cortical porosity, 14.1%), but case 2 did not (cortical width, 0.84 mm; cortical porosity, 11.6%). Trabecular connectivity of cancellous bone was preserved in both patients, with a bone volume to total volume of 18.2% in case 1 and 35.1% in case 2. Both patients had been doing daily strength training and treadmill walking (2-3 h/day) for over 10 years. Although case I showed cortical thinning and porosis, we suggest that long-term loaded exercise therapy may help to preserve cancellous trabecular bone in both hyperparathyroidism and hypoparathyroidism.

Middle ear adenoma with facial palsy: A case report and a review of the literature.

A 52-year-old man presented to our emergency department with an acute onset of right-sided facial nerve (FN) palsy of House-Brackmann grade V. Electroneurography (ENoG) was conducted with no response at the right FN, as compared with the left FN (0%). We performed a biopsy of the right middle ear mass and histological studies showed the tumor to be neuroendocrine tumors (NET) of the middle ear. We resected the tumor with canal wall down mastoidectomy and reconstructed the posterior meatal wall with soft tissue. Three months after surgery, the FN paralysis had improved with House-Brackmann grade II. We reviewed cases of NET with FN palsy, and nine patients, including our case, have been reported. Our case is the first report of ENoG for the description of FN palsy due to NET. Although the ENoG value was 0%, it was remarkably improved by surgery. The other cases of NET patients with FN palsy also recovered FN function after surgery. These results suggest that it is recommended to perform the total resection of the tumor to improve the FN function.

Dialysis-related carpal tunnel syndrome in the past 40 years.

PURPOSE AND METHOD: Patients on hemodialysis develop carpal tunnel syndrome (CTS) due to an accumulation of dialysis-related ß2 microglobulin (ß2m) amyloid (DRA). In Japan, dialysis technology has progressed remarkably in the past 40 years and has increased the time until patients require surgery for CTS. However, unclear is whether the time from the start of hemodialysis to the first surgery for CTS is associated with ß2m clearance by the different hemodialysis techniques. Therefore, we retrospectively evaluated ß2m clearance, serum ß2m levels, and the change in the length of this period in patients across 4 periods according to the year that first surgery for CTS was performed: period 1, 1982-1989; period 2, 1990-1999; period 3, 2000-2009; and period 4, 2010-2019. RESULT: A total of 222 patients who met the selection criteria were included. Mean ß2m clearance was -1.8 ± 16.7% in period 1, and improved to 65.4 ± 8.6% in period 3. Accordingly, the serum ß2m value after hemodialysis decreased significantly. The time from the start of hemodialysis to the first surgery for CTS was 12.4 ± 2.9 years in period 1 but increased to 21.8 ± 6.3 years in period 3. In multivariable linear regression analysis, the significant factors contributing to ß2m clearance were periods 2, 3, and 4. In particular, the relation between removal of ß2m and the extension of the dialysis vintage in period 1 and 2 was remarkable compared with periods 3 and 4. CONCLUSION: Our findings indicate that improvement of ß2m clearance via advances in dialysis technology might result in a significant extension in the time between starting HD and the first surgery for CTS.

Long-term use of glucocorticoid exacerbates bone lesions in postmenopausal women with rheumatoid arthritis.

Glucocorticoid-induced osteoporosis is osteoporosis arising due to long-term use of glucocorticoids. Despite decades of intense research, the effects of long-term use of glucocorticoids in humans on bone cells and bone structural changes remain unclear. We performed post-mortem histomorphometric analysis of bone from two female patients with rheumatoid arthritis aged 64 and 85 years. Our two patients had been treated with glucocorticoids for 19 and 14 years, respectively. In Case 1, all markers of cancellous bone volume were markedly decreased compared with the age-matched reference range. Connectivity of cancellous bone trabecula was absent. Only a few island bones were noted. There was prominent thinning of the cortical bone and extension of the bone marrow cavity into the cortical bone with prominent cortical porosis. Cortical nodes between the endocortical surface and the trabecula disappeared due to endocortical resorption. Stoppage of lamellar structure was observed because the bone resorption by osteoclasts surpassed bone formation by osteoblasts. Empty lacunae characterised by disappearance of osteocytes were visible. In Case 2, all volume markers of cancellous bone were decreased to the same extent as Case 1. However, cortical porosis was more prominent than Case 1. These two cases suggest that use of glucocorticoid therapy >10 years can induce severe osteoporosis in elderly rheumatoid arthritis women with higher disease activity and that the disappearance of cancellous bone is the common characteristic. The 85-year-old woman was characterised by cortical porosis.

An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs.

Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development. Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a powerful genetic tool that enables high-throughput screening of novel drug targets. The development of anti-TB drugs promises to be accelerated by CRISPRi. This study determined whether CRISPRi could be applicable for predictive screening of the combinatorial effect between major anti-TB drugs and an inhibitor of a novel target. In the checkerboard assay, isoniazid killed Mycobacterium smegmatis synergistically or additively in combinations with rifampicin or ethambutol, respectively. The susceptibility to rifampicin and ethambutol was increased by knockdown of inhA, which encodes a target molecule of isoniazid. Additionally, knockdown of rpoB, which encodes a target molecule of rifampicin, increased the susceptibility to isoniazid and ethambutol, which act synergistically with rifampicin in the checkerboard assay. Moreover, CRISPRi could successfully predict the synergistic action of cyclomarin A, a novel TB drug candidate, with isoniazid or rifampicin. These results demonstrate that CRISPRi is a useful tool not only for drug target exploration but also for screening the combinatorial effects of novel combinations of anti-TB drugs. This study provides a rationale for anti-TB drug development using CRISPRi.

Micromonosporamide A with Glutamine-Dependent Cytotoxicity from Micromonospora sp. MM609M-173N6: Isolation, Stereochemical Determination, and Synthesis.

An acyldipeptide, micromonosporamide A, was isolated from the fermentation broth of Micromonospora sp. MM609M-173N6 by bioassay-guided fractionation using a glutamine compensation assay. The planar structure was elucidated on the basis of comprehensive one- and two-dimensional nuclear magnetic resonance and high-resolution mass spectrometry. The relative and absolute configuration of the entire molecule were determined using a combined approach, involving chromatographic analysis by liquid chromatography-mass spectrometry, advanced Marfey's method, and total synthesis. Micromonosporamide A exhibited glutamine-dependent antiproliferative activity.

Case report: Osteomalacia due to bisphosphonate treatment in a patient on hemodialysis.

BACKGROUND: No publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD). CASE PRESENTATION: We report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry. CONCLUSIONS: We believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.

Characteristics of aspiration pneumonia patients in acute care hospitals: A multicenter, retrospective survey in Northern Japan.

BACKGROUND: Pneumonia is a common cause of illness and death of the elderly in Japan. Its prevalence is escalating globally with the aging of population. To describe the latest trends in pneumonia hospitalizations, especially aspiration pneumonia (AP) cases, we assessed the clinical records of pneumonia patients admitted to core acute care hospitals in Miyagi prefecture, Japan. METHODS: A retrospective multi-institutional joint research was conducted for hospitalized pneumonia patients aged ≥20 years from January 2019 to December 2019. Clinical data of patients were collected from the medical records of eight acute care hospitals. RESULTS: Out of the 1,800 patients included in this study, 79% of the hospitalized pneumonia patients were aged above 70 years. The most common age group was in the 80s. The ratio of AP to total pneumonia cases increased with age, and 692 out of 1,800 patients had AP. In univariate analysis, these patients had significantly older ages, lower body mass index (BMI), a lower ratio of normal diet intake and homestay before hospitalization, along with more AP recurrences and comorbidities. During hospitalization, AP patients had extended fasting periods, more swallowing assessments and interventions, longer hospitalization, and higher in-hospital mortality rate than non-AP patients. A total of 7% and 2% AP patients underwent video endoscopy and video fluorography respectively. In multivariate analysis, lower BMI, lower C-reactive protein, a lower ratio of homestay before hospitalization, a higher complication rate of cerebrovascular disease, dementia, and neuromuscular disease were noted as a characteristic of AP patients. Swallowing interventions were performed for 51% of the AP patients who had been hospitalized for more than two weeks. In univariate analysis, swallowing intervention improved in-hospital mortality. Lower AP recurrence before hospitalization and a lower ratio of homestay before hospitalization were indicated as characteristics of AP patients of the swallowing intervention group from multivariate analysis. Change in dietary pattern from normal to modified diet was observed more frequently in the swallowing intervention group. CONCLUSION: AP accounts for 38.4% of all pneumonia cases in acute care hospitals in Northern Japan. The use of swallowing evaluations and interventions, which may reduce the risk of dysphagia and may associate with lowering mortality in AP patients, is still not widespread.