Rendu–Osler–Weber syndrome presenting with pulmonary arteriovenous fistula

A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula.     

Alpha-thalassemia in two Mediterranean populations

We used restriction endonuclease analysis to determine the incidence of alpha-thalassemia in two Mediterranean islands. In a random population sample, the gene frequency of deletion-type alpha-thalassemia-2 (- alpha) was 0.18 in Sardinians and 0.07 in Greek Cypriots. All cases were the rightward crossover type. From these frequencies and the known incidence of hemoglobin-H disease in these populations, we calculated the frequency of the alpha-thalassemia-1 genotype (--) and determined that it was low. We also found that beta-thalassemia homozygotes in sardinia have a higher incidence of alpha-thalassemia than normals and beta thalassemia heterozygotes because a significantly greater number of these homozygotes are also homozygous for the alpha-thalassemia-2 lesion. These findings support the theory that coinheritance of alpha- thalassemia mitigates the severity of beta-thalassemia and suggest that the protection is most pronounced when two alpha-globin genes are deleted.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency

Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.     

Initial experience with a steerable, phased vector array ultrasound catheter in the GI tract

BACKGROUND: EUS requires a significant capital outlay. The ability to perform high-resolution phased array scanning and Doppler interrogation by using a catheter that interfaces with a standard US console could increase the accessibility of EUS. Recently, an electronic phased-array US catheter was developed for intracardiac use. To date, this technology has not been applied to the GI tract. The aim of this study is to determine the feasibility and imaging characteristics of a new phased array scanning US catheter in the GI tract. METHODS: Swine were placed under general anesthesia. This study used a 100 cm, 10F, torquable catheter with 4-way tip deflection to greater than 90 degrees. The catheter tip houses a phased vector array transducer with variable frequency (5.5-10 MHz) and variable focal distance. It has pulsed/color and power Doppler capability. The probe was passed through a therapeutic flexible sigmoidoscope into the upper GI tract. Acoustic coupling was achieved via a condom filled with water or by gastric water infusion. Needle visualization experiments were performed with a second endoscope (also passed per oral) with a standard EUS-guided fine needle aspiration needle. RESULTS: Acoustic coupling was easily achieved. Resolution of the GI wall into characteristic layers (esophagus 5, stomach 7) was demonstrated. At 5.5 MHz, tissue resolution and Doppler imaging were excellent to greater than 10 cm from the transducer. A 22-gauge EUS-guided fine needle aspiration needle was easily visualized at depth greater than 4 cm. Flow in gastric, hepatic, and pancreatic parenchymal vessels approximately 1 mm diameter was visualized by using power and color Doppler. CONCLUSIONS: This 10F array US catheter is capable of high-resolution two-dimensional imaging of the gut wall as well as high-quality Doppler imaging. The Doppler capabilities of this equipment may have new GI applications.     

Endosonography-guided celiac plexus neurolysis

Background: We have evaluated the safety and efficacy of performing endosonography-guided celiac plexus neurolysis (EUS CPN) in patients with pain due to intra-abdominal malignancies. Methods: Thirty patients with upper abdominal pain requiring narcotic analgesia and suspected or known intra-abdominal malignancy were selected for EUS CPN. This group included 25 patients with pancreas carcinoma and 5 patients with intra-abdominal metastases. Using the linear array ultrasound endoscope and a prototype needle catheter, transgastric injection of the celiac plexus with bupivacaine and 98% dehydrated absolute alcohol was accomplished. Results: Pain scores were significantly lower compared with baseline at 2, 4, 8, and 12 weeks after EUS CPN (median follow-up: 10 weeks). At these follow-up intervals, 82% to 91% of patients required the same or less pain medication and 79% to 88% of patients had persistent improvement in their pain score. Comparison of patients with TXNXM1 versus TXNXM0 pancreatic carcinoma revealed higher initial pain scores (7.9 ± 1.92 versus 5.8 ± 2.0, p = .02) and a greater decline in pain scores (decrease of 6.1 ± 3.1 versus 4.8 ± 2.0, p = .004). Complications were minor and consisted of transient diarrhea in four patients. Conclusion: EUS CPN is a safe and effective means for improving pain control in patients with intra-abdominal malignancy. The technique may be performed as an outpatient at the same setting as the EUS staging examination. (Gastrointest Endosc 1996;44:656-62.)     

Utility of Web-based assessment of patient satisfaction with endoscopy

OBJECTIVES: The dramatic growth of the World Wide Web (Web) holds potential for use in survey distribution and submission. Its use has not previously been studied in the context of patient satisfaction with endoscopy procedures. In this study we compared standard mail, telephone, and Web-based modes of endoscopy satisfaction survey administration with respect to response rate and response content. METHODS: An endoscopy satisfaction questionnaire consisting of seven core items from the modified Group Health Association of America (GHAA-9) was distributed to patients after routine outpatient endoscopy. Patients were randomized to receive the questionnaire by standard mail, telephone, or Web (if applicable). Response rates and satisfaction scores in the groups were compared. The nonresponders to the standard mail and Web surveys were subsequently contacted by telephone to determine their level of satisfaction. RESULTS: Response rates to the telephone survey (81% among those designated as non-Web users and 78% among Web users) and standard mail (75% non-Web users, 67% Web users) were higher than response rate to the Web-based survey (34%) (p < or = 0.0005). There was no significant difference in satisfaction scores among the groups or between satisfaction of nonresponders and responders. CONCLUSIONS: The potential of our Web-based survey was limited by poor response rates. This arose from privacy protection precautions that complicated access to the Web site. Future Web-based strategies for surveying patients will need to be more user-friendly while maintaining the intent of the recent Health Insurance Portability and Accountability Act regulations.