P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration.

Mutations in p97/VCP cause two motor neuron diseases: inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia and familial amyotrophic lateral sclerosis. How p97 mutations lead to motor neuron degeneration is, however, unknown. Here we used patient-derived induced pluripotent stem cells to generate p97 mutant motor neurons. We reduced the genetic background variation by comparing mutant motor neurons to its isogenic wild type lines. Proteomic analysis reveals that p97R155H/+ motor neurons upregulate several cell cycle proteins at Day 14, but this effect diminishes by Day 20. Molecular changes linked to delayed cell cycle exit are observed in p97 mutant motor neurons. We also find that two p97 inhibitors, CB-5083 and NMS-873, restore some dysregulated protein levels. In addition, two p97 inhibitors and a food and drug administration-approved cyclin-dependent kinase 4/6 inhibitor, Abemaciclib, can rescue motor neuron death. Overall, we successfully used iPSC-derived motor neurons, identified dysregulated proteome and transcriptome and showed that p97 inhibitors rescue phenotypes in this disease model.

Arterial stiffening and cardiac hypertrophy in a new rat model of type 2 diabetes.

BACKGROUND: We determined the effects of NIDDM on haemodynamic parameters describing arterial wall elasticity and cardiac hypertrophy in rats administered streptozotocin (STZ) and nicotinamide (NA), using the aortic impedance analysis. METHODS: Male Wistar rats at 2 months were administered intraperitoneally 180 mg kg(-1) of NA, 30 min before an intravenous injection of 50 mg kg(-1) STZ, to induce type 2 diabetes. The STZ-NA rats were divided into two groups, 4 weeks and 8 weeks after induction of diabetes, and compared with untreated age-matched controls. Pulsatile aortic pressure and flow signals were measured by a high-fidelity pressure sensor and electromagnetic flow probe, respectively, and were then subjected to Fourier transformation for the analysis of aortic input impedance. RESULTS: In each diabetic group, the experimental syndrome was characterized by a moderate and stable hyperglycaemia and a relative deficiency of insulin secretion. However, the 8-week but not the 4-week STZ-NA diabetic rats showed a decrease in cardiac output in the absence of any significant changes in mean aortic pressure, having increased total peripheral resistance. The diabetic syndrome at 8 weeks also contributed to an increase in aortic characteristic impedance, from 1.49 +/- 0.33 (mean +/- SD) to 1.95 +/- 0.28 mmHg s mL(-1) (P < 0.05), suggesting a detriment to the aortic distensibility in NIDDM. Meanwhile, the STZ-NA diabetic animals after 8 weeks had an increased wave reflection factor (0.46 +/- 0.09 vs. 0.61 +/- 0.13, P < 0.05) and decreased wave transit time (25.8 +/- 3.8 vs. 20.6 +/- 2.8 ms, P < 0.05). Ratio of the left ventricular weight to body weight was also enhanced in the 8-week STZ-NA diabetic rats. CONCLUSION: The heavy intensity with early return of the pulse wave reflection may augment systolic load of the left ventricle coupled to the arterial system, leading to cardiac hypertrophy in the rats at 8 weeks after following STZ and NA administration.

Effect of pravastatin on myocardial protection during coronary angioplasty and the role of adenosine.

Pravastatin has been shown, in an experimental model of ischemia reperfusion, to increase adenosine levels, which exert a potent and protective effect on the heart. The purpose of this study was to investigate whether pravastatin can provide cardioprotection by increased production of adenosine in patients undergoing coronary angioplasty, a clinical model of ischemia reperfusion. Thirty-five hyperlipidemic patients who underwent elective angioplasty for a major epicardial coronary artery were randomly allocated to either 3-month pravastatin or placebo before catheterization. In the placebo group, the mean ST-segment shift during the second balloon inflation was similar that observed during the first inflation, whereas in the preconditioned patients, the shift was significantly less, which is consistent with ischemic preconditioning. In the pravastatin-treated patients, the changes of ST-segment shift were similar between the first and second balloon inflations. In contrast, the patients who received aminophylline developed higher ST-segment shifts during the first and second inflations than those in the pravastatin-treated group alone. Measurements of chest pain score and myocardial lactate extraction ratios during inflation mirrored those of the ST-segment shift. The present study demonstrates that administration of pravastatin results in a significant gain in tolerance to ischemia during angioplasty. The effect of pravastatin was abolished by aminophylline, suggesting that the cardioprotective effect of pravastatin may result from activation of adenosine receptors.

Preliminary result of an algorithm to select proper ventricular assist devices for high-risk patients with extracorporeal membrane oxygenation support.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is not suitable for long-term support because of its high incidence of complications. Conversion from ECMO to ventricular assist device (VAD) is reasonable, and we have developed a simple algorithm for selecting proper VADs for these ECMO-supported patients. METHODS: We converted 12 patients who were receiving ECMO support to VAD for bridge to transplantation. Group I (n = 6) was converted directly from ECMO to VAD. Group II (n = 6) underwent stage conversion. We added left atrial drainage to ECMO because of lung edema or marked left heart distension. We discontinued drainage after recovery of right heart function. Group II had more unfavorable risk factors for VAD before ECMO. RESULTS: Three patients (50%) in Group I received biventricular VADs. The other 3 patients were converted to left ventricular assist device (LVAD), but only 1 (16.7%) experienced successful conversion. We successfully converted 5 patients (83.3%) in Group II to LVAD without right VAD, and 4 of them could be weaned from the ventilator. The multiple-organ dysfunction score gradually improved in Group II despite additional surgery. Two patients in each group received heart transplantation and survived long term. CONCLUSION: Using a conversion protocol provides a good guideline for making decisions. According to the protocol, right heart and pulmonary function can be clearly assured before shifting to LVAD in these critical ECMO-supported patients.

Conversion of extracorporeal membrane oxygenation to non-pulsatile left ventricular assist device. Is it out-of-date for non-pulsatile LVAD?

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides an immediate support for acute deterioration of hemodynamic and pulmonary status, but what is the best decision for these critical patients? Biventricular assist device (BVAD) or left ventricular assist device (LVAD)? We proposed a protocol of step-by-step conversion from ECMO to LVAD after assurance of the reversibility of right ventricle and pulmonary function. METHODS: After femoral venoarterial ECMO was inserted for the critical patients, the left atrial drainage was added to the ECMO firstly and the femoral arterial inflow was shifted to the ascending aorta for preventing possible peripheral vascular complications. Temporary clamp of right heart drainage was tried to test right heart function 24 to 48 hours later. The sweep gas flow of oxygenator could be reduced gradually to test the pulmonary function. Therefore, the right heart drain and the oxygenator could be withdrawn to become a non-pulsatile LVAD or shift to pneumatic LVAD directly. There were four clinical experiences with successful conversion without temporary right ventricular assist device. RESULTS: All of them were able to convert their ECMO to LVAD smoothly in 8.0+/-2.5 days. Three of them were shifted to non-pulsatile LVAD, and one was converted to HeartMate. All but one could be weaned from the ventilator. No BVAD was needed in these patients. Due to the shortage of donor hearts, only one had the chance to undergo heart transplantation. CONCLUSIONS: The protocol did provide a good guideline for decision-making for those under ECMO support necessitating bridge to transplantation.

New method of coronary artery occlusion for beating-heart coronary artery bypass surgery.

Temporary occlusion of the coronary artery is an essential step in beating-heart coronary artery bypass surgery. The traditional method of occlusion of the coronary artery, by looping and suspension with thread or elastic slings, carries some potential risk for damage to the vessels. We report another method for temporary coronary artery occlusion involving parallel placement of stitches with pledgets along the coronary artery distal and proximal to the target area. This offers a clean operative field by gentle occlusion of the target coronary artery.

Utilization of the aortic flap above the facing commissure in arterial switch operations.

BACKGROUND: The aortic flap above the facing commissure after removal of the coronary button from the aortic sinus can be utilized for reconstruction in an arterial switch operation. METHODS: The free flap was used to reconstruct the coronary artery in two cases, as a medially based trapdoor. A rotational flap was inserted into the cut-open right pulmonary artery to augment the neopulmonary arterial anastomotic site in another case. RESULTS: All patients are doing well at mid term follow-up. CONCLUSIONS: The indications of each method and reported tricks to avoid coronary artery kinking during an arterial switch operation are discussed.

Left anterolateral thoracotomy for simultaneous correction of ventricular septal defect and coarctation of the aorta.

Three patients with ventricular septal defect and coarctation of the aorta were treated successfully by simultaneous correction of both anomalies through a single incision via a left transsternal anterolateral thoracotomy. (Texas Heart Institute Journal 1994; 21:158-60)

Interventricular septum rupture due to falling from a height.

Non-penetrating traumatic interventricular septal rupture of the heart is rare. This lesion can result from blunt injuries, either immediate or delayed, but has never been reported from blunt chest trauma secondary to falling from height. Surgical repair can usually be done as an elective procedure with good results. However, with some patients early repair is necessary as a lifesaving measure. We report on a 15-year-old patient admitted after falling from the fourth floor with multiple bone fractures and blood pressure of 80/0. He soon required mechanical ventilation, but a heart murmur was only detected after some hours. On the fifth day a non-penetrating traumatic interventricular septal rupture became apparent, which was proved by echocardiography and Swan-Ganz catheterization. The patient underwent successful repair of the interventricular septal defect on the 13th day following injury. Two weeks later surgery for his bone fractures was carried out, after which the patient could be discharged uneventfully.

Combination of Nicks' and Konno's procedures for surgical treatment of severe congenital aortic stenosis.

This 11-year-old girl with Down's syndrome had severe aortic valvular stenosis with a pressure gradient of 95 mmHg. Balloon valvotomy failed to reduce the pressure gradient. Surgical correction was performed. The aortic valve was bicuspid with fibrotic change and the anulus was about 10 mm in diameter. The aortic valve was resected, and the anulus was enlarged by a combination of the Nicks and Konno procedures. Then, a St. Jude 19 mm mechanical prosthesis was implanted, and the right ventricular outflow tract was repaired with a baked woven Dacron patch. The postoperative course was very uneventful. She was discharged in good condition on the 10th postoperative day. A combination of the Nicks and Konno procedures is recommended to correct very small aortic anuli requiring extensive enlargement of the aortic root.

Aneurysm arising from the branch of the superior mesenteric artery.

Superior mesenteric branch aneurysms are rare and usually become symptomatic at the time of rupture. Pain, gastrointestinal blood loss and intra-abdominal hemorrhage draw attention to the presence of aneurysms in 70% of the reported cases. We report on a 64-year-old male patient who had an emergent laparotomy for acute abdominal pain at a local hospital in Changhua in March of 1988. The operative finding was an unresectable mesentric mass, and the pathologic finding of the biopsy was a chronic abscess. Because of two episodes of tarry stools after the operation, the patient was referred to the National Taiwan University Hospital for further evaluation of the intra-abdominal mass. After admission in April of 1990, abdominal sonogram and CT examinations demonstrated the presence of a multilobulated mass which was suspected to be an aneurysm. Selective superior mesenteric arteriography confirmed this diagnosis and showed that the aneurysm arose from the origin of the ileocolic branch. At surgery, the aneurysm was found to have a fistula tract communicating with the terminal ileum. The aneurysm and the associated segment of the terminal ileum were successfully removed. We herein report this unusual case.

Cystic hamartoma of the lung: report of two cases.

Two cases of cystic pulmonary hamartoma are reported with the clinical, roentgenographic and histopathologic findings. Both patients were asymptomatic, and the lesions were discovered on routine chest roentgenography. Physical examination and laboratory data revealed no significant abnormal findings, but CT scans of the chest showed cystic change in both lesions. The histopathologic pictures of the lesions were characterized by a composition of glandular bronchiolar structures lined with ciliated cuboid epithelium and fibrous connective tissue. One case demonstrated interlacing, communicating bands and whorls of smooth spindle muscle cells with elongated nuclei and rounded blunt ends. Neither the epithelial, nor muscular fibrous tissue elements exhibited any degree of anaplasia. The two patients were followed up for 10 months and 3 years, respectively. They both showed no signs of recurrence or distant metastasis.