Stereoselective synthesis of (±)-epibatidine analog: (±)-2β-(2-chloro-5-pyridinyl)-8-azabicyclo[3.2.1]octane

Stereoselective synthesis of (+/-)-epibatidine analog 2, which contains the 8-azabicyclo[3.2.1]octane ring system, was achieved by using palladium-catalyzed Heck-type coupling reaction from 3.     

Synthesis of 2′,3′-dideoxyisoguanosine from guanosine

2,3'-Dideoxyisoguanosine was synthesized from guanosine via intermediate 6-[(4-methylphenyl)thio]-2-oxo-9-(2',3',5'-tri-O-acetyl-beta-D-ribofuran osyl)-2,3-dihydropurine (4). The 2-oxo, 6-amino and 5'-hydroxy triprotected isoguanosine derivative was utilized to reduce high polarity and promote poor solubility of intermediates. The protecting groups for oxo and 6-amino were easily removed in reduction of olefin in ribose without additional reaction steps. 2',3'-Vicinal diol in ribose sugar moiety was transformed to olefin with Bu3SnH by radical reaction via bisxanthate. Removing 5'-O-TBDMS protecting group gave final product, 2',3'-dideoxyisoguanosine (12) in a 10% overall yield.     

Primary intramedullary spinal cord primitive neuroectodermal tumor with intracranial seeding in an infant

Primary spinal cord primitive neuroectodermal tumor (PNET) is a rare entity. In all, 13 cases have been reported in the literature, including 3 with intracranial seeding. A 3-month-old girl with involvement of the spinal cord below the mid-thoracic level is described. The brain MRI revealed findings indicative of seeding along the intracranial subarachnoid space. Biopsy, duraplasty and removal of laminotomy flap were done. In spite of a good response to the first cycle of postoperative 8-drugs-in-a-day chemotherapy, further treatment was refused. She died 21 days after the onset of leg weakness, which reveals the rapid progression of untreated cases. To our knowledge, this is the first case of spinal cord PNET with parenchymal involvement that has been described in an infant.     

The Gastric Bypass for Failed Bariatric Surgical Procedures

Background: Revision of failed bariatric surgical procedures is a significant challenge for every bariatric surgeon. Methods: Evaluated are surgical difficulties, management problems and weight loss in patients with distal gastric bypass as a revisionary procedure. Eighty patients were followed up to 3 years; four were lost to follow-up. Mean age was 43; mean prebariatric surgery weight 134 kg; height 1.65 meters; body mass index 40.1; ideal body weight 62.7 kg; excess weight 70.5 kg; per cent excess weight 214%. A 250 cm stomach-to-ileocecal valve segment of small bowel was used, and the biopancreatic secretions were brought into the terminal ileum 100 cm from the ileocecal valve. Mean pouch size was 63 cc; length of hospital stay 5 days; operative blood loss 616 cc; operative time 130 min. Results: Intraoperative complications included three splenic injuries (without splenectomy). Early complications included one deep vein thrombosis, two marginal ulcers, one GI hemorrhage, one wound dehiscence, one pouch outlet obstruction and one pancreatitis. Late complications included: one death from protein malnutrition/ARDS; 21 hypoproteinemia; six protein malnutrition, and of these, three had hyperalimentation; three cholecystitis; 27 anemia; 22 incisional hernia; two staple-line disruption (reoperated); 26 low serum iron; 11 prolonged (> 6 months) diarrhea; three prolonged frequent vomiting; and two unrelated deaths (chronic myelogenous leukemia and amyotrophic lateral sclerosis). Mean excess weight loss was 83% at 12 months; 89% at 24 months; and 94% at 36 months. Conclusion: The distal gastric bypass is fraught with the operative and immediate post-operative complications experienced in any revisionary bariatric surgery. Distal gastric bypass is very effective in producing long-term weight loss. Nutritional problems are common but usually easily corrected. The most serious nutritional complication is protein malnutrition, which must be identified and corrected early. Success of this procedure is dependent upon patient compliance with proper nutrition and supplements, and regular office follow-up with monitoring of laboratory data. Patients who are noncompliant are at significant risk for complications.     

Characterization of the oral absorption of several aminopenicillins: determination of intrinsic membrane absorption parameters in the rat intestine in situ

The absorption mechanism of several penicillins was characterized using in situ single-pass intestinal perfusion in the rat. The intrinsic membrane parameters were determined using a modified boundary layer model (fitted value +/- S.E.): Jmax* = 11.78 +/- 1.88 mM, Km = 15.80 +/- 2.92 mM, Pm* = 0, Pc* = 0.75 +/- 0.04 for ampicillin; Jmax* = 0.044 +/- 0.018 mM, Km = 0.058 +/- 0.026 mM, Pm* = 0.558 +/- 0.051, Pc* = 0.757 +/- 0.088 for amoxicillin; and Jmax* = 16.30 +/- 3.40 mM, Km = 14.00 +/- 3.30 mM, Pm* = 0, Pc* = 1.14 +/- 0.05 for cyclacillin. All of the aminopenicillins studied demonstrated saturable absorption kinetics as indicated by their concentration-dependent wall permeabilities. Inhibition studies were performed to confirm the existence of a nonpassive absorption mechanism. The intrinsic wall permeability (Pw*) of 0.01 mM ampicillin was significantly lowered by 1 mM amoxicillin and the Pw* of 0.01 mM amoxicillin was reduced by 2 mM cephradine consistent with competitive inhibition.     

Plasma catecholamines and oxygen consumption during weaning from mechanical ventilation

Previous studies on oxygen consumption ( ) during weaning from mechanical ventilation assumed that an increase in ( ) reflected oxygen consumption by respiratory muscles ( ), and proposed as a weaning predictor. We measured CO₂ production ( ) and plasma catecholamines in 20 short-term ventilated patients during weaning by SIMV and CPAP. as a percentage of during spontaneous ventilation ( %) ranged from 4.8% to 41.5%. also increased and correlated with . Plasma adrenaline and noradrenaline increased significantly to levels known to produce considerable increases in metabolic rate. Mean arterial pressure and heart rate concomitantly increased, but spontaneous minute ventilation decreased. Thus, since the increased plasma catecholamines are calorigenic, the assumption that represents is incorrect. Although mean % of successfully weaned patients was significantly less than that of failure-to-wean patients, the wide scatter of individual values in the latter group excludes % as an accurate weaning predictor.     

Selective neuronal survival and upregulation of PCNA in the rat inner retina following transient ischemia

In this study we investigated the extent and time course of neuronal cell death and the regulation of the proliferating cell nuclear antigen (PCNA) in the different retinal cell layers following ischemia-reperfusion injury. Retinal ischemia was induced by controlled elevation of the intraocular pressure for a duration of 60 min. Changes in thickness and cell numbers in the retinal cell layers were analyzed at various time points (1 h to 4 weeks) after reperfusion. In parallel, apoptotic cell death was determined by the TUNEL method and the expression of PCNA analyzed by immunocytochemistry. In addition, we tested whether PCNA is expressed in neurons by double immunocytochemistry. The reduction in thickness was found to be less pronounced in the inner nuclear layer (INL). Correspondingly, cell numbers decreased by only 33% in the inner retina, but by more than 80% in the outer nuclear layer (ONL). Alterations in glial cell numbers did not contribute significantly to postischemic changes in the INL and ONL as assessed by using immunocytochemical markers for microglial and Müller cells. The time course of cell death determined by the TUNEL technique also differed markedly in the retinal layers being rapid and transient in the inner retina but delayed and prolonged in the ONL. PCNA immunoreactivity was undetectable in the normal retina, but was specifically induced in neurons of the inner retina within 1 h after reperfusion and was sustained for at least 4 weeks. We conclude that in contrast to photoreceptors in the ONL, a significant proportion of inner retinal neurons is resistant to ischemic insult induced by transiently increased intraocular pressure and that PCNA may possibly play a role in the selective postischemic survival of these cells.     

The pattern of bone marrow oedema on MRI in osteonecrosis of the femoral head

It has been suggested that transient osteoporosis or the bone marrow oedema syndrome (BMOS) may be the initial phase of osteonecrosis of the femoral head (ONFH) and that there may be a common pathophysiology. In this study, we have assessed the MR images of 200 consecutive patients with ONFH in respect of the BMO pattern in order to test this hypothesis. This pattern was not observed in the early stage of ONFH. The initial abnormal finding detected on the MR images was an abnormal band of intensity at the junction between the necrotic area and the normal bone. Structural damage of the head seems to result in the appearance of the BMO pattern and the development of pain in ONFH. There was no finding to support the existence of a continuum between BMOS and ONFH.     

Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition.

Onset of the mitochondrial permeability transition (MPT) causes both necrotic and apoptotic cell death in cultured hepatocytes. Salicylate lowers the threshold for onset of the MPT. In this study, our aim was to determine whether nontoxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and tert-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2 microM), a specific inhibitor of the MPT. In hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), salicylate accelerated cell killing after low-dose TNF-alpha (1 ng/ml), which by itself induced little apoptosis. Salicylate enhancement of apoptosis was associated with onset of the MPT and accelerated caspase 3 activation. Salicylate also augmented killing of MCF-7 human breast tumor cells by etoposide and PLC/PRF/5 human hepatoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, salicylate potentiates both necrotic and apoptotic cell killing by promoting onset of the MPT. Enhancement by salicylate of MPT-dependent apoptosis may play a role in protection by aspirin and other nonsteroidal anti-inflammatory drugs against colon, lung, and breast cancer.     

Dural repair using acellular human dermis: experience with 200 cases: technique assessment

OBJECTIVE: Many craniotomies require a watertight dural closure. When primary dural repair is not possible, a graft is necessary. Autograft material is not always easily accessible or available, necessitating the use of other material. We performed 200 craniotomies using an acellular human dermal graft (AlloDerm; LifeCell Corp., The Woodlands, TX) to determine its suitability as a dural substitute. METHODS: From June 1996 through March 1998, all patients at Allegheny General Hospital who required a dural substitute graft and in whom autograft harvest was impractical or impossible received the acellular dermal autograft. The running suture technique was used to form a watertight seal. RESULTS: After follow-up for a minimum of 1 year, seven patients have required subsequent surgery. Three patients developed cerebrospinal fluid leaks that were repaired without removing the dermal graft. Four patients developed wound infections that required debridement. In each patient, the graft seemed to be uninvolved in the infectious process and was left in place. The patients were administered antibiotics postoperatively, and there have been no recurrent infections. No adhesion formation or scarring was noted around or underneath the graft in any patient. CONCLUSION: AlloDerm is a reasonable alternative to the available dural graft materials. Its handling characteristics are similar to those of dura, it is biologically inert, and it does not produce adhesion formation.