Renoprotective effects of laxative linaclotide: Inhibition of acute kidney injury and fibrosis in a rat model of renal ischemia-reperfusion.

Ischemia-reperfusion (I/R) leads to tissue damage in transplanted kidneys, resulting in acute kidney injury (AKI) and chronic graft dysfunction, which critically compromises transplant outcomes, such as graft loss. Linaclotide, a guanylate cyclase C agonist clinically approved as a laxative, has recently been identified to exhibit renoprotective effects in a chronic kidney disease (CKD) model. This study evaluates the therapeutic effects of linaclotide on AKI triggered by I/R in a rat model with an initial comparison with other laxatives. Here, we show that linaclotide administration resulted in substantial reduction in serum creatinine levels, reflective of enhanced renal function. Histological examination revealed diminished tubular damage, and Sirius Red staining confirmed less collagen deposition, collectively indicating preserved structural integrity and mitigation of fibrosis. Further analysis demonstrated lowered expression of TGF-ß and associated fibrotic markers, α-SMA, MMP2, and TIMP1, implicating the downregulation of the fibrogenic TGF-ß pathway by linaclotide. Furthermore, one day after I/R insult, linaclotide profoundly diminished macrophage infiltration and suppressed critical pro-inflammatory cytokines such as TNF, IL-1ß, and IL-6, signifying its potential to disrupt initial inflammatory mechanisms integral to AKI pathology. These findings suggest that linaclotide, with its established safety profile, could extend its benefits beyond gastrointestinal issues and potentially serve as a therapeutic intervention for organ transplantation. Additionally, it could provide immediate and practical insights into selecting laxatives for managing patients with AKI or CKD, regardless of the cause, and for those receiving dialysis or transplant therapy.

The Prognostic Nutritional Index is a Predictive Marker for Postoperative Complications in Patients with Late-Onset Ulcerative Colitis.

PURPOSE: The number of patients with late-onset ulcerative colitis (UC) requiring surgery has increased in recent years. The risk of postoperative complications is higher in the elderly, so preoperative assessment is important. We aimed to explore the performance of preoperative assessment of nutritional markers for predicting postoperative complications in patients with late-onset UC. METHODS: We retrospectively analysed 140 medically refractory UC patients who underwent surgery. The association between age at UC onset and risk of postoperative complications was explored using a fractional polynomial model. Uni- and multi-variate logistic regression analyses were performed to identify nutritional markers associated with postoperative complications. RESULTS: The polynomial model showed patients with UC onset after 50 years of age had an increased risk of postoperative complications. Late-onset (LO) UC, an onset occurring after 50 years old, was associated with a higher risk of incisional surgical site infection (SSI) and intra-abdominal abscess than early-onset (EO) UC. Compared with the EO group, the LO group had fewer nutritional markers that were significantly associated with postoperative complications. The prognostic nutritional index (PNI) was calculated using the albumin level and the total lymphocyte count, and it was the only index that was significant in the LO group (odds ratio 0.872 95% CI 0.77-0.99, P = 0.03). CONCLUSIONS: It was more difficult to use nutritional status to predict the risk of postoperative complications in patients with late-onset UC than in patients with early-onset ulcerative colitis. PNI may be a useful nutritional marker for patients with both late- and early-onset UC.

Risks and benefits of transurethral resection of the bladder tumor using photodynamic diagnosis with oral 5-aminolevulinic acid hydrochloride according to age and history of recurrence in patients with non-muscle invasive bladder cancer.

BACKGROUND: Patient selection for transurethral resection of the bladder tumor using photodynamic diagnosis (PDD-TURBT) with oral 5-aminolevulinic acid (5-ALA) hydrochloride for non-muscle-invasive bladder cancer (NMIBC) is still unclear as to the best balance of risks (adverse events including hypotension) and benefits (reduction of intravesical recurrence). METHODS: This single-center retrospective study between April 2013 and March 2022, compared the intravesical recurrence-free survival between patients who underwent PDD-TURBT and WL-TURBT using propensity score matching. RESULTS: A total of 222 patients who underwent PDD-TURBT and 177 patients who underwent WL-TURBT for NMIBC were included. Propensity score matching was used to compare intravesical recurrence-free survival in 119 NMIBC patients in the both treatment groups. The intravesical recurrence-free survival within 500 days was significantly higher in the PDD-TURBT group than in the WL-TURBT group (P = 0.039; hazard ratio [HR] 0.48 [0.23-0.98]). Subgroup analysis showed that PDD-TURBT contributed to the reduction of short-term intravesical recurrence in patients aged < 75 years (P = 0.02; HR 0.22 [0.06-0.79]) and primary disease (P = 0.038; HR 0.35 [0.13-0.94]). Hypotension with a systolic blood pressure of < 80 mmHg was observed in 79 patients (35.6%) during PDD-TURBT surgery. In particular, age ≥75 years and general anesthesia were independent prognostic factors for predicting intraoperative hypotension. CONCLUSIONS: PDD-TURBT reduced short-term intravesical recurrence in NMIBC, whereas a higher frequency of hypotension was found in patients aged ≥ 75 years. These results suggest that the risks and benefits of PDD-TURBT are well balanced in younger patients (< 75 years) and those with primary disease.

Association between amorphous calcium-phosphate ratios in circulating calciprotein particles and prognostic biomarkers in hemodialysis patients.

Calciprotein particles (CPPs) are circulating colloidal mineral-protein complexes containing crystalline and/or non-crystalline (amorphous) calcium-phosphate (CaPi). Serum CPP levels correlate with vascular stiffness and calcification in patients with chronic kidney disease (CKD). In vitro studies showed that CPPs containing crystalline CaPi were more arteriosclerogenic and inflammogenic than CPPs without containing crystalline CaPi. Thus, we hypothesized that not only the quantity but also the quality of CPPs (the phase of CaPi) might affect clinical outcomes. To test this hypothesis, we quantified amorphous CaPi ratio defined as the ratio of the amorphous CaPi amount to the total CaPi amount in serum CPPs from 183 hemodialysis patients and explored its possible correlation with serum parameters associated with prognosis of hemodialysis patients. Multivariate analysis revealed that the amorphous CaPi ratio correlated positively with hemoglobin and negatively with fibroblast growth factor-21 (FGF21), which remained significant after adjusting for the total CaPi amount. Because low hemoglobin and high FGF21 are associated with increased mortality, the present study warrants further studies to determine whether low amorphous CaPi ratio in circulating CPPs may be associated with poor prognosis in hemodialysis patients.

The prognostic impact of preoperative mean corpuscular volume in colorectal cancer.

OBJECTIVE: The relationship between preoperative mean corpuscular volume and postoperative prognosis has been reported in some cancers recently, but no certain consensus has been reached, especially for colorectal cancer. We evaluated the usefulness of mean corpuscular volume as a prognostic factor in colorectal cancer patients. METHODS: This study included 1003 patients with colorectal cancer who underwent curative surgery in a single institution. The relationship between mean corpuscular volume values and postoperative recurrence was evaluated by fractional polynomial model. Based on the result, patients were divided into groups according to mean corpuscular volume values. Clinicopathological factors and long-term outcomes were compared between the groups. RESULTS: The risk of postoperative recurrence according to mean corpuscular volume value showed a J-shaped curve, suggesting that both low and high mean corpuscular volume have high risk. Low mean corpuscular volume (≤84 fl) group was oncologically advanced in terms of pathological tumor stage, histological grade and lymphatic invasion with higher inflammation markers. High mean corpuscular volume (>95 fl) group had higher frequency of drinking habit with higher values of aspartate aminotransferase, alanine aminotransferase and γ-glutamyl transpeptidase. Abnormal mean corpuscular volume group including these two groups showed significantly worse disease-free survival than the other (P < 0.001). Multivariate analysis suggested that abnormal mean corpuscular volume was an independent risk factor for postoperative recurrence (hazard ratio, 1.344; 95% confidence interval, 1.005-1.796; P = 0.046). Furthermore, its prognostic impact was more significant in pStage III than in other stages. CONCLUSION: Preoperative low and high mean corpuscular volume is a poor prognostic factor in colorectal cancer patients. It could be a predictive marker to estimate worse survival outcome after surgery.

Acute neurological deterioration after surgical interruption of spinal dural arteriovenous fistulas: clinical characteristics, possible predictors, and treatment. Patient series.

BACKGROUND: Acute neurological deterioration develops paradoxically in some patients after obliteration of a spinal dural arteriovenous fistula (SDAVF), with thrombosis of the spinal cord veins as its primary cause. The authors aimed to clarify the clinical and radiological characteristics of acute deterioration to identify high-risk patients. They also discussed the optimal treatment for this complication. OBSERVATIONS: Ten patients with SDAVF presenting with congestive myelopathy who received microsurgical interruption were retrospectively reviewed. Severe myelopathy developed in three patients on postoperative days 1 to 3. Anticoagulation therapy was effective; however, discontinuing anticoagulants under residual spinal cord congestion caused redeterioration. These patients were characterized by significantly extended transit time on angiography and significant prolongation of spinal cord congestion. Acute deterioration exhibited a strong correlation with transit time (coefficient, 0.825; p = 0.006) and a strong correlation with spinal cord edema before surgery (coefficient, 0.656; p = 0.040). LESSONS: Acute deterioration after SDAVF treatment is likely to develop in patients with severe venous outflow impairment. Its pathology is prolonged spinal cord congestion caused by postoperative venous thrombosis and preexistent severe venous outflow impairment. Anticoagulation treatment should be continued for patients with acute deterioration until the resolution of spinal cord congestion is confirmed with magnetic resonance imaging.

The effect of lanthanum carbonate on calciprotein particles in hemodialysis patients.

BACKGROUND: Aggregation of solid-phase calcium-phosphate and fetuin-A form nanoparticles called calciprotein particles (CPP). Serum CPP levels are increased in CKD patients and correlated with vascular stiffness and calcification. In this study, we evaluated effects of lanthanum carbonate (LC) and calcium carbonate (CC) on serum CPP levels in hemodialysis (HD) patients. METHODS: Twenty-four (24) HD patients (50% men, age; 68 ± 12 years, dialysis period; 6.2 ± 4.8 years, Kt/v; 1.74 ± 0.34) were treated with CC during 0-8 weeks and then switched to LC during 9-16 weeks. Blood samples were obtained at 0, 8, 16 weeks. Serum CPP levels (TCPP) were measured by the gel-filtration method. Low-density CPP (LCPP) levels were determined by centrifuging the serum samples at 16,000 g for 2 h and measuring CPP levels in the supernatant. The difference between TCPP and LCPP was defined as the high-density CPP (HCPP) level. We evaluated association of TCPP, LCPP, and HCPP with serum calcium (Ca), phosphorus (P), intact PTH, FGF23, Klotho, fetuin-A, aortic calcification index (ACI), LDL cholesterol, and hs-CRP. RESULTS: TCPP and LCPP levels were significantly decreased after switching CC to LC, whereas Ca and P levels were not changed. HCPP levels were below the lower limit quantification in all patients. The changes in P, Ca × P, LDL cholesterol, but not ACI and the changes in hs-CRP, were correlated with the change in TCPP levels. CONCLUSION: The TCPP levels were significantly decreased after switching CC to LC. Non-calcium-containing phosphate binders may be preferable for lowering CPP levels.

Anti-TNF-α Agent Infliximab and Splenectomy Are Protective Against Renal Ischemia-Reperfusion Injury.

BACKGROUND: Renal ischemia-reperfusion (I/R) injury is associated with delayed graft function and results in poor long-term graft survival. We previously showed that splenectomy (SPLN) protects the kidney from I/R injury and reduces serum TNF-α levels. Herein, we further investigated the effects of SPLN on inflammatory responses and tissue injury in renal I/R by examining the expression of major inflammatory cytokines and heat shock protein 70 (HSP70). Because it was shown previously that the anti-TNF-α agent infliximab (IFX) attenuated renal I/R injury, we also investigated whether IFX administration mimics the effects of SPLN. METHODS: The left renal pedicles of adult male Wistar rats were clamped for 45 minutes and then reperfused for 24 hours; right nephrectomy and SPLN were performed immediately. A separate cohort was administered IFX 1 hour before surgery in lieu of SPLN. RESULTS: Serum creatinine and blood urea nitrogen levels were markedly elevated by I/R injury; these increases were significantly reversed by IFX. Furthermore, IFX inhibited the induction of inflammatory cytokines and HSP70 during renal I/R injury. Time-dependent profiles revealed that the expression of inflammatory cytokines was elevated immediately after I/R, whereas levels of HSP70, serum creatinine, and blood urea nitrogen began to rise 3 hours postreperfusion. Macrophages/monocytes were significantly increased in I/R-injured kidneys, but not in those administered IFX. The outcomes of SPLN mirrored those of IFX administration. CONCLUSIONS: Splenectomy and TNF-α inhibition both protect the kidney from I/R injury by reducing the accumulation of renal macrophages/monocytes and induction of major inflammatory cytokines.

Tumoral calcinosis involving the cervical spine.

BACKGROUND: Tumoral calcinosis (TC) is a disease of unknown etiology characterized by the presence of calcified masses in the juxta-articular regions of the extremities. Involvement of the cervical spine is very rare. In this report, the characteristics of TC of the cervical spine, including the clinical presentation, radiographic features, and surgical management are discussed. CASE DESCRIPTION: A 90-year-old healthy female suffering from numbness of the upper extremities for 3 months presented with a 2-week history of progressive weakness of the lower extremities. A neurological examination revealed mild weakness and sensory impairment of the bilateral upper and lower extremities. Computed tomography (CT) scans demonstrated amorphous calcified masses posterior to the spinous process that extended into the interlaminar spaces of C3/4 and C4/5. The masses involved the posterior elements of C3-C4. Interestingly, CT scans performed 4 years earlier showed subtle calcification of a yellow ligament at C3/4 and C4/5. However, neither calcified masses nor bone erosion were observed. On magnetic resonance (MR) imaging, the mass showed hypointensity on T1- and T2-weighted images. The lesion was compressing the spinal cord and was resected surgically. The pathological findings were consistent with those of TC. The natural history of TC is not understood. However, this case suggests that calcified masses may progress within several years and that the bone around the mass may be involved. Postoperatively, residual masses may disappear spontaneously, while new bone is formed in the erosive lamina and facet. CONCLUSION: The treatment of choice for TC, if the lesion causes progressive symptoms, is surgical resection.

[Long-term Results Regarding the Instability of Decompressive Surgery without Fusion for Degenerative Spondylolisthesis].

PURPOSE: The long-term results of decompressive surgery for degenerative spondylolisthesis (DS) were evaluated with reference to instability. MATERIALS AND METHODS: Patients (n=48) undergoing decompressive surgery without fusion were studied. The diagnosis of spondylolisthesis was made based on the presence of sagittal vertebral slippage greater than 3mm. Instability was defined as translation more than 2mm on lateral functional radiography. Surgical interventions were divided into two groups: bilateral laminotomy (n=25)and laminectomy (n=23). Clinical results were evaluated according to the McCulloch's classification and Japanese Orthopedic Association(JOA)score. RESULTS: Of 48 patients, 25 showed preoperative instability. Eleven patients showed both pre-and postoperative instability. The mean pre-and postoperative slippages were 7.5 and 7.6mm, respectively. Of 23 patients without preoperative instability, nine developed postoperative instability. In this group, slippage changed from 6.2 to 6.1mm. Instability was not related to slippage progression. Surgical results of patients undergoing laminotomy were superior to those undergoing laminectomy. The mean pre-and postoperative JOA scores and recovery rate were 14.5, 20.9, and 63.1 in instability group patients with laminotomy and 15.6, 23.2, and 59.0 in the non-instability group, respectively. Surgical results were similar and not related to preoperative instability. Low back pain (LBP) showed no correlation to the degree of slippage, instability, and surgery type. LBP improved in each group. CONCLUSIONS: Instability, defined by vertebral translation on lateral functional radiography, did not affect the surgical results of patients with DS treated with laminotomy.

[Long-term results of decompressive surgery without fusion for degenerative spondylolisthesis].

PURPOSE: The long-term results of decompressive surgery for degenerative spondylolisthesis with symptomatic lumbar spinal stenosis were evaluated retrospectively with regard to the postoperative progression of slippage and clinical symptoms. MATERIALS AND METHODS: The study included 53 patients who underwent surgery, and for whom follow-up of at least 5 years was conducted. Spondylolisthesis was diagnosed based on the presence of sagittal vertebral translation greater than 3mm on lateral radiographs. The patients were divided into two groups:Group I:37 patients undergoing bilateral laminotomy, and Group II:16 patients undergoing laminectomy. The clinical results were evaluated according to McCulloch's classification and the Japanese Orthopaedic Association(JOA)score. RESULTS: The mean pre-and postoperative JOA scores were 14.6 and 22.9 in Group I and 14.7 and 21.0 in Group II, respectively. The JOA scores improved soon after surgery, after which the scores declined gradually in both groups. The recovery rate was 63.0% in Group I and 43.7% in Group II. The average amount of pre- and postoperative slippage was 7.3mm and 6.9mm in Group I and 6.2mm and 6.9mm in Group II, respectively. In Group I, the slippage progressed within the first year, after which the degree of slippage slowly decreased to lower values than those observed preoperatively, whereas slippage progressed for 5 years before declining in Group II. No correlations were observed between progression of slippage and clinical outcomes in either group. CONCLUSIONS: Laminotomy produces satisfactory long-term results both clinically and radiographically in patients with degenerative spondylolisthesis.

[Transcranial motor evoked potentials monitoring for cerebral aneurysm surgery].

OBJECTIVE: To evaluate the usefulness of transcranial motor evoked potential(MEP)monitoring for aneurysm surgery. METHODS: Sixty-four patients undergoing aneurysm surgery were included in the study. We recorded MEP responses at craniotomy, when dissecting the aneurysm and surrounding tissue, after clipping, and during temporary clipping of the parent artery. We examined the relations between MEP wave pattern change and postoperative motor function. RESULTS: In all of the patients MEPs were recordable for continuous neurophysiological monitoring of the vascular territory of interest throughout the surgery. In 16 patients, significant intraoperative MEP changes occurred. Of these patients, three patients presented with postoperative transient motor deficit. From the changes in MEP wave recording after aneurismal clipping and temporary occlusion of the parent artery. We speculated that the maximal time allowed for occlusion of the perforating arteries without ischemic damage is five minutes. Intraoperative MEP changes had a sensitivity of 100%(3/3)and specificity of 78.7%(48/61). The positive predictive value of postoperative motor deficit was 18.8%(3/16), and the negative predictive value was 100%(48/48). It was important to carry out MEP monitoring, so as not to produce false-negatives. CONCLUSIONS: Intraoperative transcranial MEP monitoring is useful for predicting motor function after aneurysm surgery.

Deterioration after surgical treatment of spinal dural arteriovenous fistula associated with spinal perimedullary fistula.

Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of vascular malformations of the spine and are defined as abnormal arteriovenous shunts within the dura. SDAVFs are considered to be acquired and should be distinguished from congenital intradural perimedullary arteriovenous fistulas (PMAVFs). A 32-year-old female presented with both SDAVF and PMAVF, manifesting as a slowly progressive paraparesis over a 6-month period. Initial spinal angiography demonstrated an SDAVF in the sacral region and was terminated with incomplete demonstration of all segmental arteries. The fistula was obliterated by surgery and the patient showed transient postoperative improvement followed by delayed deterioration 2 months later. Magnetic resonance (MR) imaging showed many hypointense flow voids around the cord. The second angiography verified a PMAVF in the lumbar region and complete obliteration of the SDAVF. The fistula was closed by surgery and the patient improved slightly. Surgical results of SDAVFs are generally good. Therefore, if a patient fails to improve or deteriorates further after surgery with persistent perimedullary vessel abnormalities on MR imaging, the possibility of reopening of the fistula or the presence of another fistula should be considered and repeat angiography must be performed, especially if the initial angiography was incomplete.

Increment of absolute neutrophil count in the third trimester and increased risk of small-for-gestational-age birth: Hirakata Risk Associated with Pregnancy Assessment Research (HIRAPAR).

OBJECTIVE: Small-for-gestational-age (SGA) infants, who have growth restriction, have higher perinatal morbidity and mortality. Excessive inflammatory reaction such as neutrophil activation has been observed in pregnant women whose offspring had restricted fetal growth, but the association between white blood cell (WBC) counts and SGA birth has not yet been assessed. We therefore examined the association of WBC count and its change with the risk of SGA birth. STUDY DESIGN: We enrolled 2356 pregnant women who had full-term singleton delivery at a private maternity hospital in Hirakata, Japan. SGA was defined as under the 10th percentile of birthweight for gestational age, baby sex, and mother's parity according to the Japanese neonatal anthropometric charts renewed in 2010. Blood samples were measured in the first and third trimesters. We performed multiple logistic regression analysis to assess associations between total and differential WBC counts and SGA birth. RESULTS: Women with SGA birth tended to have higher total WBC count in the third trimester compared with women who did not have SGA birth. This tendency was not observed for total WBC count in the first trimester. After adjustment for age, height, body mass index at entry, smoking habit, weekly gestational weight gain, and pregnancy-induced hypertension, higher total WBC count in the third trimester was associated with an increased risk of SGA birth. Total WBC count in the first trimester did not show any significant association with SGA birth. The ratio of total WBC count in the third trimester to that in the first trimester was associated with SGA birth; the odds ratio for 1 unit increase was 3.02 (95% CI: 1.54-5.92). Regarding differential WBC counts in the third trimester, neutrophil count but not lymphocyte count was associated positively with SGA birth. CONCLUSIONS: Higher total WBC and absolute neutrophil counts in the third trimester were associated with SGA birth. In addition, greater ratio of increase in total WBC counts during pregnancy showed a positive association with the incidence of SGA birth. These associations may reflect a vicious cycle of inflammation and placental dysfunction as a cause of fetal growth restriction.

Gestational bodyweight gain among underweight Japanese women related to small-for-gestational-age birth.

AIM: The prevalence of underweight women, who have an increased risk for small-for-gestational-age (SGA) birth, is increasing in Japan. We examined the associations of pre-pregnancy body mass index and gestational weight gain (GWG) with SGA birth among Japanese women. MATERIAL AND METHODS: We conducted a prospective cohort study of 1391 women who delivered full-term singleton babies. SGA was defined as below the 10th percentile of birthweight at each gestational age, baby sex, and parity. We calculated the 5th percentile of birthweight in the same way for another threshold for SGA. According to pre-pregnancy body mass index, we divided the participants into three groups: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), and overweight and obese (≥25.0 kg/m(2)). RESULTS: SGA birth was observed most frequently among the underweight group (13.8%). Underweight was associated with an increased risk of SGA birth. The multiple-adjusted odds ratio for underweight was 1.96 (95% confidence interval, 1.23-3.11) compared with normal weight. Sufficient GWG reduced the incidence and the multiple-adjusted odds ratio for 1-kg increase of GWG was 0.86 (0.81-0.92). The same tendency was observed for the delivery of infants below the 5th birthweight percentile. Women with underweight and normal weight who had 9.0 kg or less of GWG had a significantly higher risk of SGA birth than women with normal weight who had 9.1-11.0 kg of GWG. CONCLUSIONS: Underweight and poor GWG were associated with a higher incidence of SGA birth. However, the incidence of SGA birth among underweight women was not increased significantly if they had sufficient GWG.