Results of contracture tests with halothane,caffeine, and ryanodine depend on different malignant hyperthermia-associated ryanodine receptor gene mutations

BACKGROUND: More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine. METHODS: Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 microm ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene. RESULTS: In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene. CONCLUSIONS: The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans.     

Retrograde intrarenal surgery (RIRS). Technical complement for cases of acute lithiasis

IntroductionWashing the renal cavities using minipercutaneous surgery shaft is an ideal technical procedure for retrograde intrarenal surgery (RIRS) when lithiasic fragmentation is significant or if the anatomy of the renal cavities may obstruct the spontaneous elimination of fragments.Materials and methodswe performed 37 RIRS on 35 patients with renal lithiasis (14 men, 21 women) with a mean age of 56 (range 33-72) years, divided into two groups in accordance with the size of their kidney stones. Group A, 23 patients with lithiasis <1.5 cm; Group B, 12 cases with lithiasis >1.5 cm. 28 patients had a single kidney stone and 7 had multiple stones. Approach: Flexible uretrorenoscopy, 7.5 Fr (Flex-X(®, Karl Storz) by means of a ureteral access sheath. Holmium laser lithotripsy (Calculase®, Karl Storz) using 200 and 365 micrometer fibres. Fragment extraction with 1.7 Fr nitinol baskets (N-gage, Cook). In cases of significant fragmented stone burden, the renal cavities were washed with low-pressure fluid irrigation using a ureteral access sheath, which was collected together with the stone fragments carried by the “mini-perc” sheath (Ultrax-x® 18Fr, Cook; Rusch, 14 Fr) placed under radiologic and endoscopic control at the level of the calyx-papilla selected for fragment drainage.Resultsthe mean diameter for group A was 9.13 (range 5-13) mm and 20.25 (range 16-28) mm for group B. The overall mean operating time was 81 (range 30-160) min. Group A required 66.43 ± 35.18 min. and group B 107.5 ± 46.73 min. (p = 0.006). The rate of absence of stones immediately after surgery was 83.2%, 93.1% at 3 months (95.6% for A and 83.3% for B; p = 0.217). In no case was ureteral stenosis observed as a result of the use of ureteral access sheaths. In 7 group B patients (58.3%) with acute lithiasis and/or alteration in their pyelocaliceal anatomy, we performed active lavage of the renal cavities applying the aforementioned percutaneous technique. The mean post-surgery hospital stay was 2.1 (range 1-4) days. There were post-surgery complications (Clavien 1) in 7 patients (20%). Two patients required a second FURS.ConclusionsRIRS can be effective treatment for renal lithiasis >1.5 cm. Lavage of the renal cavities helps to eliminate stone fragments, reducing the possibility of retreatment.     

Pharmacokinetics of Oxaliplatin During Open Versus Laparoscopically Assisted Heated Intraoperative Intraperitoneal Chemotherapy (HIPEC): An Experimental Study

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated for patients with minimal residual or no residual disease after primary surgery and chemotherapy for stage III ovarian carcinoma. The technical feasibility of the laparoscopic approach for HIPEC has been demonstrated in a previous study. An experimental study on the porcine model was carried out to compare oxaliplatin pharmacokinetics during a laparoscopic-assisted procedure versus the coliseum technique for HIPEC.

Methods

Adult pigs received an HIPEC procedure that was based on 460 mg/m² of oxaliplatin over 30 minutes with a perfusate heated at 41°C to 43°C. The HIPEC drains were placed in the upper and lower quadrants of the abdomen. Peritoneal fluid and blood samples were collected every 10 minutes during the procedure, and the pharmacokinetics of oxaliplatin was studied.

Results

Two groups of 10 adult pigs were studied. All the procedures were successfully completed with an adequate intra-abdominal temperature and distribution. No major technical problems were encountered. At the end of the HIPEC, 41.5% of the molecule was absorbed in the laparoscopic group compared with 33.4% in the laparotomy group (P = .0543). Peritoneal oxaliplatin half-life (T_½) was significantly faster in the laparoscopic procedure (median, 37.5 vs. 59.3 minutes, P = .02). The area under the curve ratio of peritoneal to plasma reflects a more important oxaliplatin crossing through the peritoneal barrier in the laparoscopic procedure (ratio, 16.4 in the closed procedure vs. 28.1 in the open one; P = .03).

Conclusions

This study confirms the technical feasibility and reliability of the laparoscopic approach for HIPEC, and it extends knowledge concerning peritoneal drug absorption. Oxaliplatin absorption is far higher with laparoscopy in terms of time course in peritoneal perfusion. Clinical application in selected patients may be expected after further experimental investigation designed to define the adequate drug dosage.

     

The impact of stenosis and translation on spinal cord injuries in traumatic cervical facet dislocations

BACKGROUND CONTEXT

Although facet dislocations account for only 6% of cervical trauma, the consequences are often devastating. Cervical facet dislocations are associated with a disproportionate amount of spinal cord injuries; however, neurologic examination of patients is often difficult, as patients commonly present with reduced levels of consciousness. There are limited studies that have investigated the impact of spinal canal diameter and translation on neurologic injury following facet dislocations.

Endoscopic resection of granular cell tumors in the gastrointestinal tract: a single center experience

Background

The frequency of granular cell tumors (GCTs) identified in the gastrointestinal tract has recently increased with the increased use of routine endoscopy. Endoscopic treatment is increasingly used as an alternative to traditional surgical resection, but there are few reports on the efficacy, safety, and long-term prognosis of endoscopic treatment for GCTs. The aim of this study was to assess the efficacy, safety, and long-term prognosis of endoscopic resection for the gastrointestinal GCTs.

Methods

We examined a total of 27 GCTs in 25 patients who were treated by endoscopic resection from January 2007 to February 2011. For endoscopic resection, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) was used.

Results

Twenty GCTs were located in the esophagus, 5 in the stomach, and 2 in the colon. The median size of the GCTs was 10 mm; the largest size, located in the ascending colon, measured 18 mm. EMR with a ligation device was performed in 20 cases, conventional EMR in 5 cases, and ESD in 2 cases. En bloc resection was performed in 25 cases (92.6 %), and endoscopic complete resection piecemeal resection was achieved in 25 cases (92.6 %). Pathologic complete resection was achieved in 22 lesions (81.5 %). Intraprocedural bleeding was noted in three patients, with no occurrence of perforation or postprocedure stricture. No recurrence was observed during the mean follow-up period of 15 months (range 9–31 months).

Conclusions

Endoscopic resection appears to be a safe and effective treatment for GCTs in the gastrointestinal tract.     

Treatment of proximal humeral fractures with Polarus nail fixation

A chart review of 20 patients who sustained acute proximal humeral fractures and who were treated by surgical stabilization with locked antegrade humeral intramedullary nails (Polarus nails) was undertaken. The clinical outcome measurements were fracture healing, infection, and neurologic injury. Radiologic outcome measurements included fracture alignment, loosening, fixation and hardware failure, and malunion and nonunion. Of 20 fractures, 11 healed without complications. The mean immediate postoperative and final radiographic valgus neck/shaft angulation measured 131 degrees. Of the 20 implants, 3 had proximal fixation screw loosening. Of the 20 implants, 2 underwent revision surgery for proximal fixation failure. With certain fracture types, the Polarus intramedullary humeral nail can be an effective implant. In fracture cases involving an unstable or comminuted lateral metaphyseal fracture, if the starting point extends into the greater tuberosity, fixation failure or fracture displacement may result.     

Intramedullary nailing of distal metaphyseal tibial fractures

BACKGROUND: The treatment of distal metaphyseal tibial fractures remains controversial. This study was performed to evaluate the results of intramedullary nailing of distal tibial fractures located within 5 cm of the ankle joint. METHODS: Over a sixteen-month period at two institutions, thirty-six tibial fractures that involved the distal 5 cm of the tibia were treated with reamed intramedullary nailing with use of either two or three distal interlocking screws. Ten fractures with articular extension were treated with supplementary screw fixation prior to the intramedullary nailing. Radiographs were reviewed to determine the immediate and final alignments and fracture-healing. The Short Form-36 (SF-36) and Musculoskeletal Function Assessment (MFA) questionnaires were used to evaluate functional outcome. RESULTS: Acceptable radiographic alignment, defined as <5 degrees of angulation in any plane, was obtained in thirty-three patients (92%). No patient had any change in alignment between the immediate postoperative and the final radiographic evaluation. Complications included one deep infection and one iatrogenic fracture at the time of the intramedullary nailing. Six patients could not be followed. The remaining thirty fractures united at an average of 23.5 weeks. Three patients with associated traumatic bone loss underwent a staged autograft procedure, and they had fracture-healing at an average of 44.3 weeks. The functional outcome was determined at a minimum of one year for nineteen patients and at a minimum of two years (average, 4.5 years) for fifteen patients. At one year, there were significant limitations in several domains despite fracture union and maintenance of alignment, but there was improvement in the MFA scores with time. CONCLUSIONS: Intramedullary nailing is an effective alternative for the treatment of distal metaphyseal tibial fractures. Simple articular extension of the fracture is not a contraindication to intramedullary fixation. Functional outcomes improve with time.     

Human epidermal growth factor receptor 3 in head and neck squamous cell carcinomas

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptor (HER) family. The main characteristic of HER3 is that it does not possess tyrosine kinase activity, unlike other HERs. The role of HER3 in tumorigenesis has now been recognized, particularly in head and neck squamous cell carcinomas (HNSCCs). Despite conflicting studies, HER3 was found to be overexpressed in HNSCC samples, and correlates with disease progression and poor survival, especially when it is coexpressed with other HERs. HER3 is a significant factor in HNSCC treatment resistance. Indeed, HER3 is a major mechanism described for cetuximab resistance because of modification of epidermal growth factor receptor (EGFR) internalization and by phosphotidylinositol‐3‐kinase (PI3K)/AKT signaling pathway activation. HER3 also affects resistance to tyrosine kinase inhibitors (TKIs) and thereby promotes treatment escape and radiotherapy resistance by activation of the survival signaling pathway. To counteract this, pharmacologic inhibitors of HER3 are currently in development and could significantly improve HNSCC treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38 : E2412–E2418, 2016     

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.     

Molecular mechanisms in hormone-resistant prostate cancer

Prostate cancer is the most common malignancy in males. Despite the efforts for an early diagnosis, approximately one third of the cases are diagnosed in advanced clinical stages. Prostatic cancer, as the function of normal prostate is dependent upon androgens. So, androgenic deprivation represents an effective treatment especially in advanced cases. Although, the majority of patients will initially respond to androgen blockade, consequently the hormone-resistance will develop and the tumor will progress. The mechanism that determines tumoral progression during the endocrine treatment is driven by genomic instability, characterized by activating mutations of androgen receptor gene (AR), progression of some cellular clones possible of neuroendocrine origin that become adapted to low concentrations of residual adrenal androgens, suppression of apoptosis, by bcl-2 oncogene overexpression and p53 mutations, and growth factors (IGF-1--Insulin-like growth factor, KGF--keratinocyte growth factor, EGF--Epidermal growth factor, TGF a, b- Transforming growth factor a and b, bFGF--Fibroblastic growth factor type b) regulatory effect through either a paracrine or an autocrine mechanism. The identification of molecular alterations that appear during prostate carcinogenesis, may lead to the identification of new molecular targets to prevent hormone-resistance and to improve the prognosis in prostate cancers.