Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.

Primary CNS lymphoma.

Primary CNS lymphoma (PCNSL) is seen with increasing frequency in both immunocompetent and immunocompromised patients. Radiation therapy has historically been standard treatment for this disease, resulting in complete remissions in the majority of patients, but with most patients relapsing and dying of the disease in less than 2 years. The use of chemotherapy appears to be changing the natural history of this tumor, with significantly prolonged survival in some groups of patients. The optimal agents, doses, schedules, routes of administration, and need for radiation therapy, however, remain undefined. In this review, some of the questions regarding the management of PCNSL are addressed and recommendations are made regarding the design of future regimens.

Prediction of late enophthalmos by volumetric analysis of orbital fractures.

The purpose of this study was to determine whether orbital volume assessment by computerized tomography (CT) could provide additional information for the initial evaluation of orbital blowout fractures and guide optimal treatment. The medical records of 30 patients with orbital blowout fractures, either surgically or conservatively managed, were retrospectively reviewed. Orbital volumetric analysis was then determined from digitized CT scans. Fracture-related volume expansion relative to the unaffected fellow orbit was correlated with motility deficits and location and degree of enophthalmos. Early Hertel's measurements (< 4 weeks) were available in 21 patients and did not correlate with the computer volumetric values or with subsequent late enophthalmos. Late Hertel's measurements (> 4 weeks) were obtained in 13 of 15 nonrepaired fractures and in 5 of 15 surgically repaired patients (late presentation; 18 patients). When seen at more than 4 weeks, 11 (92%) of 12 patients with > or = 13% orbital volume expansion manifested significant enophthalmos (> 2 mm) compared with 1 (17%) of 6 patients with < 13% orbital expansion (p = 0.004). Fractures presenting with enophthalmos on initial examination had extensive medial wall involvement in addition to the floor fracture (p = 0.003). CT measurements of orbital volume can predict the final degree of late enophthalmos and may facilitate the planning of surgical intervention.

Ethical and intellectual property in the biological sciences.

Ethical concerns on patents in the biological sciences are increased by the prospect of patents for higher life forms. A Canadian patent grants the owner the right to exclude others in Canada from making, using, or selling or offering for sale his or her invention for the term of the patent; however, it does not give the patent owner any positive rights to do likewise. As with other forms of property, the right to make, use, or sell a patented invention may be regulated by other laws or guidelines. In Canada, higher life forms, medical and surgical methods are not patentable subject matter. Unicellular life forms and subcellular material are considered patentable. Decisions on ethical issues are not considered by patent officers. The Patent Office is guided only by legislation. Other regulations by the legislatures can direct public policy and minimize risks.

Pericardial sclerosis as the primary management of malignant pericardial effusion and cardiac tamponade.

OBJECTIVES: The management of malignant pericardial effusion remains controversial. We present our experience with 93 patients referred for drainage and sclerosing procedures between 1979 and 1994. METHODS: With continuous electrocardiographic monitoring, a Kifa catheter was inserted percutaneously into the pericardial sac and allowed to drain. A 100 mg dose of lidocaine hydrochloride was instilled intrapericardially, followed by 500 to 1000 mg tetracycline or doxycycline hydrochloride in 20 to 50 ml normal saline solution. The catheter was clamped for 1 to 2 hours and then reopened, and the procedure was repeated daily until the net drainage was less than 25 ml in 24 hours. RESULTS: Subjects included 53 women and 40 men (median age 58 years). Eight patients could not undergo sclerosis because of technical failure. Eighty-five patients underwent sclerosis and required a median dose of 1500 mg of the sclerosing agent (range 500 to 700 mg), given in a median of three injections (range one to eight). Complications included pain (17 patients), atrial arrhythmias (eight patients), fever with temperature greater than 38.5 degrees C (seven patients), and infection (one patient). Two patients had cardiac arrest before sclerosis could be attempted. Sixty-eight patients (73%) had the effusion controlled for longer than 30 days, for an overall control rate of 81%. Seven other patients had control of the effusion but died of progressive malignant disease in less than 30 days. The overall median survival was 98 days (range 1 to 1724 days). Comparison of these results with outcomes reported for patients with malignant pericardial effusion who underwent surgical drainage indicates that drainage and sclerosis provide similar survivals but sclerosis carries lower morbidity, mortality, and recurrence rates. CONCLUSION: Percutaneous drainage and sclerosis constitutes a safe and effective treatment for malignant pericardial effusion. Surgical management should be reserved for the small percentage of cases that cannot be controlled by this method.

Granulomatous idiopathic orbital inflammation.

One category of idiopathic orbital inflammation (IOI) displays a granulomatous inflammatory pattern that mimics sarcoidosis, although this has not been extensively addressed in most published series of IOI. We analyzed the clinicopathologic features of patients with biopsy-proven noninfectious granulomatous inflammation of the orbit. Review of surgical pathology records from January 1988 to May 1992 identified 12 patients with a diagnosis of sarcoidosis or other noninfectious granulomatous process involving the orbit. Clinical records were reviewed, and the patients' physicians contacted to determine if the diagnosis of sarcoidosis was confirmed. Five cases in which the systemic diagnosis was not established despite thorough evaluation are reported here. We report five cases of noninfectious IOI in which sarcoidosis was suspected clinically and histologically. In these, however, further systemic evaluation at 15 to 32 months (mean 22.4) failed to reveal evidence of systemic involvement. A spectrum of histopathologic patterns was seen, including non-necrotizing foreign body type granulomas, lipogranulomatous inflammation, and variable sclerosis. Patients with solitary orbital noncaseating granulomatous inflammation should be thoroughly evaluated before a diagnosis of sarcoidosis is made. Practitioners should be aware of the existence of granulomatous IOI not associated with systemic sarcoidosis as a distinct clinicopathologic entity.

Increased disease susceptibility of transgenic tobacco plants with suppressed levels of preformed phenylpropanoid products.

It has been proposed that natural products synthesized by plants contribute to their resistance to pests and pathogens. We show here that transgenic tobacco plants with suppressed levels of the phenylpropanoid biosynthetic enzyme phenylalanine ammonia-lyase (L-phenylalanine ammonia-lyase, EC 4.3.1.5) and correspondingly low levels of chlorogenic acid, the major soluble leaf phenylpropanoid product, exhibit more rapid and extensive lesion development than wild-type plants after infection by the virulent fungal pathogen Cercospora nicotianae. These observations provide direct evidence that phenylpropanoid products contribute to disease limitation. No induction of transcripts encoding phenylalanine ammonia-lyase or the lignin branch pathway enzyme caffeic acid O-methyltransferase was observed during the infection and there was no perturbation in the pattern of soluble phenylpropanoids. Hence, increased disease susceptibility does not involve inhibition of a pathogen-induced response but likely reflects inhibition of the developmental accumulation of chlorogenic acid. Demonstration of the contribution of such preformed protectants to plant health identifies attractive targets for manipulation by breeding or gene transfer to reduce the quantitative impact of disease.

Extensin and Phenylalanine Ammonia-Lyase Gene Expression Altered in Potato Tubers in Response to Wounding, Hypoxia, and Erwinia carotovora Infection.

Potato (Solanum tuberosum L.) tubers are susceptible to infection by Erwinia carotovora, causal agent of bacterial soft rot, when wounded and subjected to wet, hypoxic environments. The expression of two putative plant defense genes, extensin and phenylalanine ammonia-lyase (PAL), was examined by monitoring their respective mRNA levels and cell wall hydroxyproline levels in tuber tissues under various conditions leading to susceptibility or resistance and after inoculation with E. carotovora in order to assess the possible roles of these genes and their products in this plant-pathogen interaction. Extensin and PAL mRNA levels as well as cell wall hydroxyproline levels accumulated markedly in response to wounding and subsequent aerobic incubation. Extensin and PAL mRNA levels as well as cell wall hydroxyproline levels decreased in response to wounding and subsequent anaerobic incubation; these changes were correlated with high susceptibility of tuber tissue to E. carotovora infection. Inoculation of wound sites with E. carotovora caused some additional accumulation of the wound-regulated extensin and PAL mRNAs under certain aerobic conditions, but never under anaerobic conditions.

Isolation and characterization of multiply antibiotic-resistant Clostridum perfringens strains from porcine feces.

Multiply antibiotic-resistant strains of Clostridium perfringens were isolated from porcine feces. Strains that were resistant to tetracycline, erythromycin, clindamycin, and lincomycin were isolated, but no penicillin- or chloramphenicol-resistant strains were obtained. Typical minimal inhibitory concentrations for resistant strains were 16 to 64 mug of tetracycline per ml, 64 to >128 mug of erythromycin per ml, >/=128 mug of lincomycin per ml, and 16 to 128 mug of clindamycin per ml. Resistance to erythromycin was always associated with resistance to lincomycin and clindamycin. Minimal inhibitory concentrations were determined for 258 strains from six farms that used antibiotics in their feeds and 240 strains from five farms that did not use antibiotics. The results show that 77.9 and 22.7% of the strains from the former farms were resistant to tetracycline and erythromycin-clindamycin-lincomycin, respectively. The comparable data from the latter farms were 25.0 and 0.8%, respectively. Agarose gel electrophoresis failed to reveal a plasmid band that was common to the resistant strains but absent in the susceptible strains. Attempts to transfer tetracycline, erythromycin, and clindamycin resistance from one strain, CW459, were not successful. Antibiotic-susceptible mutants were not isolated from this strain, despite the use of a variety of curing agents.