Preliminary Clinical Experience with a High-Definition Three Dimensional Exoscope for Spinal Surgery.

We retrospectively evaluated spinal surgeries performed using the high-definition three-dimensional exoscopic system, which became available at our institution in August 2020. Eleven patients (4 with cervical disease and 7 with lumbar disease) underwent surgery with the system. There were no surgical complications related to the system, and the results were satisfactory. The small, flexible camera of the exoscope allows the surgeon to view the surgical field from various angles, facilitating both the approach and technique. In addition, it allows the surgeon to operate in an upright position without strain on the head and neck. Although further surgical experience is needed, this system has the potential to improve the visualization of the surgical field in spinal surgery.

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

Femoral varus derotational osteotomy without pelvic osteotomy in nonambulatory children with cerebral palsy: Minimum 5 years follow-up.

ABSTRACT: Whether femoral varus derotational osteotomy (VDRO) alone or a combination of femoral and pelvic osteotomies should be performed for hip dislocation in nonambulatory children with cerebral palsy (CP) remains controversial. Few studies have reported radiographical results after the surgical treatment in nonambulatory children with CP. This study aimed to assess the results and determine predictors indicating progressive hip subluxation and redislocation after VDRO without pelvic osteotomy. We retrospectively analyzed 22 hips in 15 nonambulatory children with CP. All patients underwent VDRO without pelvic osteotomy and were followed up for at least 5 years. The mean follow-up period was 7.3 ±â€Š1.9 years. In radiological assessments, we investigated migration percentage (MP), center-edge angle, neck-shaft angle, teardrop distance, break in Shenton's line (SL), sharp's angle, acetabular ridge angle (ARA), and the change ratio of MP (Change MP). We classified patients with an MP of <40% at final follow-up in the Good group and those with an MP of ≥40% in the Poor group. The Good group included 10 children (14 hips), and the Poor group included 8 children (8 hips). No preoperative differences were found in the means of all the radiographical parameters. However, MP was significantly different between the groups from 1 year postoperatively. ARA showed improvement 5 years after surgery in the Good group. Change MP in the Good group was maintained from immediately after surgery to the final follow-up. Multivariate logistic regression analyses revealed that preoperative break in SL and Change MP immediately after surgery were parameters to predict MP at the final follow-up. In the receiver operating characteristic analysis, the cut-off values were estimated to be 19.2 mm for preoperative SL and 79.0% for Change MP immediately after surgery. Within 7.3 years of follow-up, 63.6% of the patients who underwent VDRO without pelvic osteotomy had good results. Preoperative SL and postoperative Change MP can be considered as predictors of postoperative subluxation and/or dislocation.

Angulated Salter osteotomy in the treatment of developmental dysplasia of the hip.

Salter osteotomy is widely used to improve acetabular coverage in the treatment of developmental dysplasia of the hip. Herein we describe angulated Salter osteotomy (ASO) as the modified Salter osteotomy, which creates a two-point contact between the proximal and distal fragments and better stabilizes the fixation of the fragments. We reported our results of ASO and compared it with that of Salter osteotomy performed previously by us. We retrospectively reviewed 41 unilateral hips that underwent ASO, with no other accompanying procedures, between 2012 and 2018. We investigated the radiographic measurements included the preoperative values of the acetabular index and center-edge angle (CEA), immediate postoperative values of distance d (lateral displacement of the distal fragment), lateral rotation angle (LRA), the ratio of the obturator height (ROH), pelvic height increase percentage (PHIP) and the values of acetabular index and CEA during the last follow-up. Measurements were compared with 20 unilateral hips that underwent Salter osteotomy. The mean age at the time of surgery was 5.4 years, and the mean follow-up duration was 3.3 years. Immediately after surgery, the mean distance d, LRA, ROH and PHIP were 8 mm, 19°, 70 and 1%, respectively. The last follow-up values of acetabular index and CEA significantly improved from the preoperative values by 18° and 21°, respectively. Patients treated with ASO showed significantly larger distance d, more improvement in CEA, and lesser PHIP than those treated with Salter osteotomy. The short-term outcomes of ASO are favorable. ASO was as effective as or better than Salter osteotomy in pulling out and stabilizing the distal fragment anterolaterally. ASO prevents elongation of the ilium, which causes pelvic obliquity.

Factors Contributing to Satisfaction with Changes in Physical Function after Orthopedic Surgery for Musculoskeletal Dysfunction in Patients with Cerebral Palsy.

BACKGROUND: The recognition of required treatments for cerebral palsy (CP) patients, including orthopedic surgery, differs according to region. This study was performed to identify factors associated with satisfactory changes in physical function after orthopedic surgery. METHODS: 358 patients were selected for the questionnaire survey. The following information was collected: gender, primary disease, age of initial surgery, total procedural count, operated sites, satisfaction of postoperative rehabilitation frequency, ideal amount of postoperative rehabilitation sessions per week, frequency of voluntary home training per week, satisfaction of the timing of surgery and the current satisfaction with the changes in physical function after the orthopedic surgery. We classified the patients into the satisfied and dissatisfied group according to satisfactory changes in physical function after the surgery. We performed unpaired t-tests and chi-square tests to determine the variables that differed significantly between the groups. Variables with a p value of <0.2 were included in the multivariate logistic regression analysis. RESULTS: The logistic model was revised and summed up to two potential predictors of postsurgical satisfaction with physical function: satisfaction with the frequency of postoperative rehabilitation sessions and the orthopedic surgery of the hip (distinction hit ratio, 75.4%). CONCLUSIONS: This study demonstrated that the frequency of postoperative rehabilitation and history of hip surgery seemed to be related to the satisfaction with the changes in physical function after orthopedic surgery.

Transposition osteotomy of the acetabulum for advanced-stage osteoarthritis of the hips.

BACKGROUND: Transposition osteotomy of the acetabulum (TOA) was the first periacetabular osteotomy in which the acetabulum was transposed with articular cartilage. TOA improves coverage of the femoral head and joint congruity. The purpose of this study was to investigate whether TOA is an appropriate option for treating osteoarthritis of the hips at the advanced stage by comparing it with matched control hips at the early stage. METHODS: Between 1998 and 2001, TOA was performed in 104 hips of 98 patients. Altogether, 16 of 17 hips (94%) with osteoarthritis at the advanced stage were examined and compared with 37 matched control hips at the early stage. The mean age at the operation was 48 years (38-56 years), and the mean follow-up period was 88 months (65-107 months). RESULTS: TOA corrected the acetabular dysplasia and significantly improved containment of the femoral head. Clinical scores were also significantly improved in both groups. In the advanced osteoarthritis cases, there was a tendency for abduction congruity before transposition osteotomy of the acetabulum to reflect the clinical outcome. CONCLUSIONS: TOA is a promising treatment option for advanced osteoarthritis of the hips as well as for patients at an early stage when preoperative radiographs show good congruity or containment of the joint.

The evaluation of gastric cancer sensitivity to 5-FU/CDDP in terms of induction of apoptosis: time- and p53 expression-dependency of anti-cancer drugs.

Clinical in vivo and in vitro studies have revealed pronounced gastric cancer activity using the combination of 5-fluorouracil (5-FU) and cisplatin (CDDP). In addition, the combination of 5-fluorouracil plus cisplatin (FP treatment) possesses synergistic cytotoxicity against gastric cancer. Sensitivity of two gastric cancer cell lines to anti-cancer drugs, 5-fluorouracil (5-FU) and/or cisplatinum (CDDP), was evaluated by use of either flow cytometric analysis (FACS) or morphological observation in terms of induction of apoptosis. In morphological observation, a new experimental technique was used in which cancer cells were distributed in thin collagen gel as one or two cell layers, and cultured with anti-cancer drugs. Thereafter, cells were stained with fluorescent Hoechst 33258 (Ho) and photographed, then stained with hematoxylin and eosin (H&E) and photographed again. Cell death patterns were determined by combining observations of Ho- and H&E-stained cells. While combined administration of 5-FU and CDDP did not induce apoptosis of MKN-28 (mutant-type p53), apoptotic cells were markedly observed in the case of MKN45 (wild-type p53). In addition, consecutive administration of CDDP for 3 h and 5-FU for 21 h effectively induced apoptosis of MKN45. These results indicated that the type of p53 expression in cancer cells could be a promising factor in predicting response to FP therapy and the administration of CDDP prior to 5-FU may be more effective in inducing apoptosis of gastric cancer cells with wild-type p53 expression. These data may provide evidence to support the idea that p53 expression is related to multidrug resistance (MDR) in FP therapy of gastric cancer cell lines.

Apoptosis induced by 5-fluorouracil, cisplatin and paclitaxel are associated with p53 gene status in gastric cancer cell lines.

In a recent study, we evaluated the efficacy and toxicity of 5-fluorouracil (5-FU), cisplatin (CDDP), and 5-FU plus CDDP (FP treatment) in gastric cancer cell lines and examined the relationship between the response to FP treatment and apoptosis. Our study indicated that there may be prognostic value in measuring p53 prior to FP treatment, and that cancers with wild-type p53 may be better candidates for FP treatment than those with mutant-type p53 in gastric cancer patients. In the present study, because cells with mutant-type p53 are suggested to be less responsive to FP chemotherapy treatment, we examined the relationship between the response to paclitaxel and apoptosis in MKN45 and MKN28 human gastric cancer cell lines by flow cytometry. In both MKN45 and MKN28 cells, paclitaxel arrested cells in the G2/M phases of the cell cycle after 24 h. Additionally, in both MKN45 and MKN28 cells, paclitaxel produced a significant rise in the number of subG1-phase cells after 72 h by the flow cytometry histogram. From these results, our previous study suggests that cells with mutant-type p53 may be less responsive to FP treatment and the present study indicates that another anti-cancer drug like paclitaxel, which might be mediated by a p53-independent pathway, should be selected. These insights may provide a new strategy for gastric cancer chemotherapy, especially second-line chemotherapy or adjuvant chemotherapy.

p53 dependence and apoptosis in response to FP treatment with p53-transfected colon cancer cell lines by use of thin layer collagen gel.

The combination of 5-fluorouracil (5-FU) plus Cisplatin (CDDP) (FP treatment) possesses synergistic cytotoxicity against colon cancer. The molecular mechanisms by which chemotherapeutic agents induce apoptosis have been clarified by identifying apoptosis-related genes such p53 and bcl-2. We previously established a new experimental technique in which cancer cells are distributed in thin collagen gel as 1 or 2 cell layers. additionally, we evaluated the efficacy and toxicity of FP treatment in the gastric and colon cancer cell lines, and examined the relationship between the response to FP treatment and apoptosis. In these results we reported transfection of normal p53 gene into p53 mutant and analyzed the impact of the p53 gene in a sensitivity test. In this study, we examined induced apoptosis in colon cancer cell lines and the status of p53 expression in response to treatment of HCT116, COLO320, SW480 and DLD1 with 5-FU alone, CDDP alone and FP treatment under flow cytometric analysis. Transfection of SW480 and DLD1 cells was performed to compare the chemosensitivity of naturally occurring mutant-type p53 SW480 and DLD1 cells with neo-transfected SW480 and DLD1 cells and transfected SW480 and DLD1 cells. Appreciable apoptosis was induced in HCT116 and COLO320 (p53 wild-type) but not in SW480 and DLD1 cells (p53 mutant-type). Transfected SW480 and DLD1 cells underwent significantly more apoptosis (p

Expression of p53 protein as a predictor of the response to 5-fluorouracil and cisplatin chemotherapy in human gastrointestinal cancer cell lines evaluated with apoptosis by use of thin layer collagen gel.

Apoptosis of the target cells is an important index in the assessment of the efficacy of cancer chemotherapy. We previously established a new experimental technique in which cancer cells are distributed in thin collagen gel as one or two cell layers, and cultured with anti-cancer drugs. The cells are stained with fluorescent Hoechst 33258 (Ho) and photographed, then with hematoxylin and eosin (H&E) and again photographed. The results show that most cell death patterns can be determined by combining observations of Ho and H&E-stained cells without the necessity for judging the apoptosis by electron microscopy. 5-fluorouracil (5-FU) and cisplatin (CDDP) are important anti-cancer drugs in the treatment of a variety of cancers. 5-FU or CDDP alone have shown significant effects in the treatment of gastric and colon cancers, and in addition, it has been shown that the combination of 5-FU plus CDDP (FP) therapy produces synergism greater than 5-FU or CDDP alone in gastrointestinal cancer. In this study, we evaluated the efficacy and toxicity of FP therapy in the gastric cancer cell lines MKN45, MKN28, and KATOIII and the colon cancer cell lines HCT116 and COLO320, and examined the relationship between the response to FP therapy and apoptosis. Additionally, we performed transfection of normal p53 gene into p53 mutant MKN28 cells and analyzed the impact of the p53 gene on a sensitivity test. Wild-type p53 in MKN45, HCT116, and COLO320 cells underwent significantly (p<0.01) more apoptosis than MKN28 and KATOIII cells possessing p53 mutant- and deficient-type, respectively, in FP therapy. Transfection of p53 to MKN28 cells resulted in a significantly (p<0.01) higher apoptotic index. From these results, we conclude that the p53 pathway allows induction of apoptosis in gastrointestinal cancers in FP therapy treatment, and that identification of the p53 type of a patient's cancer can be used to predict the success of FP therapy.

Ileal perforation in a patient with high spinal cord injury: report of a case.

Assessing abdominal complications in patients who have previously suffered high spinal cord injury is very difficult because the resultant loss of sensory, motor, and reflux function of the abdominal wall can mask the typical signs of acute abdomen such as tenderness, muscle rigidity, and peritoneal rebound pain. We recently diagnosed a small intestinal perforation in a 77-year-old man with a C6-7 spinal cord injury sustained 14 years earlier. The patient was correctly diagnosed as having an acute abdominal condition, despite palsy of abdominal wall sensation. An emergency laparotomy was done and a 40-cm length of affected ileum, about 180 cm distal to the Treitz ligament, including a 1-cm perforation, was resected, followed by an end-to-end anastomosis. We report this case to raise awareness of the need for appropriate diagnosis and early surgical treatment of abdominal complications in spinal-cord-injured patients.

[Relation between p53 expression of human colon cancer cell lines and induction of apoptosis by anticancer drugs].

The relation between p53 expression of human colon cancer cell lines and induction of apoptosis by anticancer drugs was examined experimentally. HCT116 had wild-type p53 expression and 5-fluorouracil (5-FU) in combination with cisplatinum (CDDP) increased both Sub G1 DNA content and the proportion of apoptotic cells. However, solitary administration of these drugs altered neither. Alternatively, for SW480 with mutant-type p53 expression, both combined administration and solitary administration of anticancer drugs showed minimal effect on Sub G1 DNA content and proportion of apoptotic cells. These results indicate that the type of p53 expression might play an important role in the determination of response to low-dose CDDP + 5-FU therapy in colon cancer patients.

Association of tannins and related polyphenols with the cyclic peptide gramicidin S.

The association of 10 different tannins and related polyphenols with gramicidin S, a cyclic peptide having a rigid beta-turn structure, has been examined using 1H-NMR spectroscopy. In the presence of pentagalloylglucose and epigallocatechin-3-O-gallate, the proton signals due to proline and the adjacent phenylalanine moieties selectively shifted to up field, suggesting a regioselective association with the beta-turn structure. The association was also supported by the observation of intermolecular nuclear Overhauser effects between epigallocatechin-3-O-gallate and the peptide. In contrast, ellagitannins, biogenetically derived from pentagalloylglucose, showed small and non-selective chemical shift changes, suggesting that interaction with these tannins is relatively weak. The hydrophobicity of the tannin molecules and the steric hindrance of the interaction site are thought to be important in the association.