An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy.

BACKGROUND: High glucose and angiotensin-II (Ang-II) levels are the known important mediators of diabetic nephropathy. However, the effects of these mediators on matrix metalloproteinase-2 (MMP-2) and on tissue inhibitor of metalloproteinase-2 (TIMP-2) in proximal tubule cells have yet to be fully examined within the context of early stage diabetic nephropathy. METHODS: In this study, we attempted to characterize changes in MMP-2 and TIMP-2 in streptozotocin-induced diabetic rats. To further examine the molecular mechanisms involved, we evaluated the effects of high glucose (30 mM) or Ang-II on MMP-2, TIMP-2 and collagen synthesis in proximal tubule cells, and investigated whether MMP-2 and TIMP-2 are regulated via the TGF-beta1 pathway. RESULTS: In streptozotocin-induced diabetic rats, TIMP-2 mRNA and protein levels were significantly higher than in controls. Urinary protein excretion also showed a significant positive correlation with glomerular and tubular TIMP-2 protein expressions, and a negative correlation with MMP-2 expression. In cultured cells, both high glucose and Ang-II induced significant increases in TGF-beta1, TIMP-2, and in collagen synthesis, and significant decreases in MMP-2 gene expression and activity, and thus disrupted the balance between MMP-2 and TIMP-2. Moreover, treatment with a selective angiotensin type 1 (AT1) receptor antagonist significantly inhibited Ang-II mediated changes in TGF-beta1, MMP-2, TIMP-2, and in collagen production, suggesting the role of the AT1 receptor. The addition of exogenous TGF-beta1 produced an effect similar to those of high glucose and Ang-II. Furthermore, the inhibition of TGF-beta1 protein prevented Ang-II-induced MMP-2 and TIMP-2 alterations, suggesting the involvement of a TGF-beta1 pathway. CONCLUSIONS: High glucose or Ang-II treatment induce alterations in MMP-2 and TIMP-2 balance, which favour TIMP-2 over-activity. Moreover, Ang-II-mediated changes in the productions of MMP-2 and TIMP-2 occur via AT1 receptors and a TGF-beta1-dependent mechanism. These results suggest that an imbalance between the MMP-2 and TIMP-2, caused primarily by an increase in TIMP-2 activity, contributes to the pathogenesis of diabetic nephropathy.     

The utility of bipolar electrocautery in hereditary hemorrhagic telangiectasia

OBJECTIVE: The surgical treatment of epistaxis associated with hereditary hemorrhagic telangiectasia (HHT) is varied. Laser therapy is often inadequate for larger complex lesions. This study sought to determine if bipolar cautery can be effectively and safely used in treating HHT-associated epistaxis. STUDY DESIGN AND SETTING: Records from all patients with HHT treated surgically over 8 years were reviewed retrospectively. Outcomes or complications were noted in the clinic on follow-up evaluation. RESULTS: Twenty-seven patients with HHT who underwent surgical treatment of epistaxis were evaluated; 18 were treated with bipolar cautery. Forty-two separate bipolar treatments were performed. No new septal perforations or synechiae were noted. Twenty-two of 42 treatments were coupled with ancillary laser treatments. The bipolar was also used as the sole technique in 20 procedures. CONCLUSION: Bipolar electrocautery is a safe and effective tool for the intraoperative control of HHT-related epistaxis. SIGNIFICANCE: Bipolar electrocautery may be used as an adjunct to laser techniques or as a stand-alone technique. EBM RATING: C-4.     

Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 +/- 4 mg/dl) or hypoglycemia (plasma glucose 58 +/- 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patients.     

Laparoscopic extended (subtotal) distal pancreatectomy with resection of both splenic artery and vein

Background

Spleen-preserving distal pancreatectomy can be performed safely and effectively by resecting both splenic vessels (Warshaw procedure) [1–4]. This simplified spleen-preserving technique might also be applied to minimally invasive distal pancreatectomy of benign and borderline malignant tumor [5, 6].

Methods

Although the conservation of both splenic vessels is paramount to preserving the spleen during laparoscopic distal pancreatectomy, preservation of the splenic vessels is not always possible, especially under the following conditions: (1) relatively large tumor, (2) associated with chronic pancreatitis, (3) tumor abutting splenic vascular structures, and (4) bleeding during the splenic vessel conserving procedure, which are potential indications of laparoscopic extended Warshaw procedure. Patient preparation and position was the same as that described in our previous study [7].

Results

During the study’s time period, 38 consecutive patients underwent laparoscopic spleen-preserving distal pancreatectomy. Of those, five patients underwent a laparoscopic extended Warshaw procedure, which all included among 16 patients of extended distal pancreatectomy by dividing the pancreas at the pancreatic neck. All patients were women with a median age of 55 (range, 38–75) years. Median total operation time and blood loss were 215 (range, 200–386) minutes and 100 (range, 0–300) ml, respectively. The median length of hospital stay was 8 (range, 5–15) days. All of postoperative complications (two grade A and two grade B postoperative pancreatic fistula; one grade A bleeding) were able to be treated conservatively. During the median follow-up period of 11 (range, 7–42) months, one focal splenic infarction and one gastric varix were noted; however, no clinically significant complications were reported.

Conclusions

Laparoscopic spleen-preserving extended distal pancreatectomy with resection of both the splenic vessels is feasible and safe [8]. This surgical technique is thought to increase the chance of preservation of the spleen with minimally invasive distal pancreatectomy in well-selected benign or borderline malignant tumor of the distal pancreas.     

Postoperative Complications Influence Prognosis and Recurrence Patterns in Periampullary Cancer

Background

The present study was performed to elucidate the influence of postoperative complications on the prognosis and recurrence patterns of periampullary cancer after pancreaticoduodenectomy (PD).

Methods

Clinical data were reviewed from 200 consecutive patients who had periampullary cancer and underwent PD between October 2003 and July 2010, and survival outcomes and recurrence patterns were analyzed. Postoperative complications were classified according to a modification of Clavien’s classification.

Results

Overall, 86 major complications of grade II or higher occurred in 71 patients. The patients were classified into two groups according to the presence of postoperative complications of grade II or higher: group Cx?, absence of complications (n = 129); and group Cx+, presence of complications (n = 71). There were no differences in gender, mean age, tumor node metastasis stage, biliary drainage, type of resection, and radicality between the two groups (P > 0.05). The 3-year overall and disease-free survival rates of the group Cx+ patients (31.0 and 22.3 %, respectively) were significantly lower than those of the group Cx? patients (49.0 and 40.0 %; P = 0.003 and 0.002, respectively). The multivariate analysis showed that postoperative complications (P = 0.001; RR = 1.887; 95 % confidence interval [CI] 1.278–2.785), a T stage of T3 or T4 (P = 0.001; RR = 2.503; 95 % CI 1.441–4.346), positive node metastasis (P = 0.001; RR = 2.093; 95 % CI, 1.378–3.179), R1 or R2 resection (P = 0.023; RR = 1.863; 95 % CI 1.090–3.187), and angiolymphatic invasion (P = 0.013; RR = 1.676; 95 % CI 1.117–2.513) were independent prognostic factors for disease-free survival. Regarding recurrence patterns, group Cx+ patients exhibited more distant recurrences than did group Cx? patients (P = 0.025).

Conclusions

Postoperative complications affect prognosis and recurrence patterns in patients with periampullary cancer after PD.     

Oncologic Outcomes after Adjuvant Chemotherapy Using FOLFOX in MSI-H Sporadic Stage III Colon Cancer

Background

Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy.

Methods

We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease.

Results

Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease-free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437).

Conclusions

Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients.     

Dorsal suspension for Morton’s neuroma: A comparison with neurectomy

BackgroundThe purpose of this study was to investigate and compare the clinical outcomes of dorsal suspension with those of neurectomy for the treatment of Morton’s neuroma.MethodsWe conducted a retrospective study of dorsal suspension and neurectomy group. The dorsal suspension was performed by dorsal transposition of neuroma over the dorsal transverse ligament after neurolysis. The visual analog scale (VAS), the Foot and Ankle Ability Measure (FAAM), postoperative satisfaction, and complications were evaluated.ResultsBoth groups reported significant pain relief, and there were no significant differences between the groups with respect to postoperative pain. The postoperative FAAM outcomes showed no significant between-group differences. Satisfaction analysis showed ‘excellent’ and ‘good’ results in the dorsal suspension and neurectomy groups (95% and 77.7%, respectively). Complications of numbness and paresthesia reported in the dorsal suspension group (5% and 5%, respectively) were significantly fewer than those of neurectomy group (61.1% and 33.3%, respectively) (both, p < .05).ConclusionsWith its favorable results, dorsal suspension can be another operative option for the treatment of Morton’s neuroma.Level of Evidence: Level III, retrospective comparative case series.     

Evaluation of Heat Generation in Unidirectional Versus Oscillatory Modes During K‐Wire Insertion in Bone

Heat generation during insertion of Kirschner wires (K‐wires) may lead to thermal osteonecrosis and can affect the construct fixation. Unidirectional and oscillatory drilling modes are options for K‐wire insertion, but understanding of the difference in heat generation between the two modes is lacking. The goal of this study was to compare the temperature rise during K‐wire insertion under these two modes and provide technical guidelines for K‐wire placement to minimize thermal injury. Ten orthopedic surgeons were instructed to drill holes on hydrated ex vivo bovine bones under two modes. The drilling trials were evaluated in terms of temperature, thrust force, torque, drilling time, and tool wear. The analysis of variance showed that the oscillatory mode generated significantly lowered peak bone temperature rise (13% lower mean value, p = 0.036) over significantly longer drilling time (46% higher mean time, p < 0.001) than the unidirectional mode. Drilling time had significant effect on peak bone temperature rise under both modes (p < 0.001) and impact of peak thrust force was significant under oscillatory mode (p < 0.001). These findings suggest that the drilling mode choice is a compromise between peak temperature and bone exposure time. Shortening the drilling time was the key under both modes to minimize temperature rise and thermal necrosis risk. To achieve faster drilling, technique analysis found that “shaky” and intermittent drilling with moderate thrust force are preferred techniques by small vibration of the drill about the K‐wire axis and slight lift‐up of the K‐wire once or twice during drilling. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1903–1909, 2019     

Radiological and clinical long-term results of heterotopic ossification following lumbar total disc replacement

Background

The long-term results of heterotopic ossification (HO) following lumbar total disc replacement (TDR) and the corresponding clinical and radiological outcomes are unclear.