Recurrent acute and chronic pancreatitis in two brothers with familial chylomicronemia syndrome

The chylomicronemia syndrome is well recognized as a rare etiologic factor of acute pancreatitis; however, whether hypertriglyceridemia can cause chronic pancreatitis (CP) remains unclear. We describe the long-time course of 2 brothers with the familial chylomicronemia syndrome caused by identical compound heterozygous mutations in the lipoprotein lipase (LPL) gene with markedly reduced LPL activity. Other etiologic factors were excluded, including mutations in the PRSS1, SPINK1, and CFTR gene. Although both brothers had recurrent acute pancreatitis and the same LPL genotype, CP became evident in only one patient. Progression to CP was associated with a more severe disease course. Thus, the chylomicronemia syndrome may cause CP in the absence of other known causative factors, and similar to alcoholic and hereditary CP, a more severe disease course is associated with disease progression.

The effects of dexmedetomidine/remifentanil and midazolam/remifentanil on auditory-evoked potentials and electroencephalogram at light-to-moderate sedation levels in healthy subjects

Avoidance of excessively deep sedation levels is problematic in intensive care patients. Electrophysiologic monitoring may offer an approach to solving this problem. Since electroencephalogram (EEG) responses to different sedation regimens vary, we assessed electrophysiologic responses to two sedative drug regimens in 10 healthy volunteers. Dexmedetomidine/remifentanil (dex/remi group) and midazolam/remifentanil (mida/remi group) were infused 7 days apart. Each combination of medications was given at stepwise intervals to reach Ramsay scores (RS) 2, 3, and 4. Resting EEG, bispectral index (BIS), and the N100 amplitudes of long-latency auditory-evoked potentials (ERP) were recorded at each level of sedation. During dex/remi, resting EEG was characterized by a recurrent high-power low-frequency pattern which became more pronounced at deeper levels of sedation. BIS Index decreased uniformly in only the dex/remi group (from 94 +/- 3 at baseline to 58 +/- 14 at RS 4) compared to the mida/remi group (from 94 +/- 2 to 76 +/- 10; P = 0.029 between groups). The ERP amplitudes decreased from 5.3 +/- 1.3 at baseline to 0.4 +/- 1.1 at RS 4 (P = 0.003) in only the mida/remi group. We conclude that ERPs in volunteers sedated with dex/remi, in contrast to mida/remi, indicate a cortical response to acoustic stimuli, even when sedation reaches deeper levels. Consequently, ERP can monitor sedation with midazolam but not with dexmedetomidine. The reverse is true for BIS.

Biphosphonate-associated osteonecrosis of the maxilla. Case report and review of the literature

In recent years, a growing number of reports in the literature have linked osteonecrosis of the jaw bones with intravenously administered bisphosphonates prescribed for the treatment of hypercalcemia of malignancy due to bone lesions of multiple myeloma or bone metastases in patients with breast or prostate cancer. Furthermore, an association between chronic oral bisphosphonate use in patients with osteoporosis or Paget's disease, and bone necrosis in the mandible or maxilla has been demonstrated in numerous case reports and case series in the last couple of years. Therapeutically, osteonecrosis of the jaws seems to be difficult to treat surgically, often resulting in a recurring or even progressing lesion. In the present case report of a bisphosphonate-associated osteonecrosis of the maxilla in a patient with osteoporosis, the current literature will be discussed, and open research questions and potential problems for our daily dental practice routine will be addressed.

Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review

OBJECTIVE: To review the efficacy of pharmacological prevention of serious reactions to iodinated contrast media. DESIGN: Systematic review. DATA SOURCES: Systematic search (multiple databases, bibliographies, all languages, to October 2005) for randomised comparisons of pretreatment with placebo or no treatment (control) in patients receiving iodinated contrast media. Review methods Trial quality was assessed by all investigators. Information on trial design, population, interventions, and outcomes was abstracted by one investigator and cross checked by the others. Data were combined by using Peto odds ratios with 95% confidence intervals. RESULTS: Nine trials (1975-96, 10 011 adults) tested H1 antihistamines, corticosteroids, and an H1-H2 combination. No trial included exclusively patients with a history of allergic reactions. Many outcomes were not allergy related, and only a few were potentially life threatening. No reports on death, cardiopulmonary resuscitation, irreversible neurological deficit, or prolonged hospital stays were found. In two trials, 3/778 (0.4%) patients who received oral methylprednisolone 2x32 mg or intravenous prednisolone 250 mg had laryngeal oedema compared with 11/769 (1.4%) controls (odds ratio 0.31, 95% confidence interval 0.11 to 0.88). In two trials, 7/3093 (0.2%) patients who received oral methylprednisolone 2x32 mg had a composite outcome (including shock, bronchospasm, and laryngospasm) compared with 20/2178 (0.9%) controls (odds ratio 0.28, 0.13 to 0.60). In one trial, 1/196 (0.5%) patients who received intravenous clemastine 0.03 mg/kg and cimetidine 2-5 mg/kg had angio-oedema compared with 8/194 (4.1%) controls (odds ratio 0.20, 0.05 to 0.76). CONCLUSIONS: Life threatening anaphylactic reactions due to iodinated contrast media are rare. In unselected patients, the usefulness of premedication is doubtful, as a large number of patients need to receive premedication to prevent one potentially serious reaction. Data supporting the use of premedication in patients with a history of allergic reactions are lacking. Physicians who are dealing with these patients should not rely on the efficacy of premedication.

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer

Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.

Different vascular smooth muscle cell apoptosis in the human internal mammary artery and the saphenous vein. Implications for bypass graft disease

BACKGROUND: The remarkable patency of internal mammary artery (MA) grafts compared to saphenous vein (SV) grafts has been related to different biological properties of the two blood vessels. We examined whether proliferation and apoptosis of vascular smooth muscle cells (VSMC) from human coronary artery bypass vessels differ according to patency rates. METHODS AND RESULTS: Proliferation rates to serum or platelet-derived growth factor (PDGF)-BB were lower in VSMC from MA than SV. Surface expression of PDGF beta-receptor was slightly lower, while that of alpha-receptor was slightly higher in MA than SV. Cell cycle distribution, expression of cyclin E, cdk2, p21, p27, p57, and cdk2 kinase activity were identical in PDGF-BB-stimulated cells from MA and SV. However, apoptosis rates were higher in MA than SV determined by lactate dehydrogenase release, DNA fragmentation, and Hoechst 33258 staining. Moreover, caspase inhibitors (Z-VAD-fmk, Boc-D-fmk) abrogated the different proliferation rates of VSMC from MA versus SV. Western blotting and GSK3-beta kinase assay revealed lower Akt activity in VSMC from MA versus SV, while total Akt expression was identical. Adenoviral transduction of a constitutively active Akt mutant abrogated the different proliferation rates of VSMC from MA versus SV. CONCLUSIONS: Higher apoptosis rates due to lower Akt activity rather than different cell cycle regulation account for the lower proliferation of VSMC from MA as compared to SV. VSMC apoptosis may protect MA from bypass graft disease.

Periapical surgery and the maxillary sinus: radiographic parameters for clinical outcome

OBJECTIVE: To find out whether conventional periapical radiographs can be used to determine the risk of creating an oroantral communication (OAC) while performing periapical surgery on maxillary premolars and molars. STUDY DESIGN: One hundred thirteen periapical radiographs of maxillary premolars and molars with periapical radiolucencies indicating chronic apical periodontitis were retrospectively analyzed and classified. The surgery reports were evaluated for occurrence of perforation of the maxillary sinus and postoperative complications. RESULTS: Perforation of the sinus membrane (also referred to as the Schneiderian membrane) occurred in 12 cases (9.6%). Exposure of the membrane without rupture occurred in 15 cases (12%). It was found that the distance between the apex or the periapical lesion and the sinus floor did not serve as a predictor of a possible sinus membrane rupture. On the other hand, if the radiograph showed a distinct distance between the lesion and the sinus floor, there was an 82.5% probability that OAC would not occur. Additionally, a blurred radiographic outline of the periapical lesion did not indicate an increased risk of sinus membrane rupture. CONCLUSION: Conventional periapical radiographs cannot be used as predictors for perforation of the maxillary sinus during periapical surgery. However, radiographs with a specific distance between the periapical lesion and the sinus floor point toward a very low risk of accidental sinus perforation during periapical surgery.

Establishment of murine cell lines by constitutive and conditional immortalization

Mouse cell lines were immortalized by introduction of specific immortalizing genes. Embryonic and adult animals and an embryonal stem cell line were used as a source of primary cells. The immortalizing genes were either introduced by DNA transfection or by ecotropic retrovirus transduction. Fibroblasts were obtained by expression of SV40 virus large T antigen (TAg). The properties of the resulting fibroblast cell lines were reproducible, independent of the donor mouse strains employed and the cells showed no transformed properties in vitro and did not form tumors in vivo. Endothelial cell lines were generated by Polyoma virus middle T antigen expression in primary embryonal cells. These cell lines consistently expressed relevant endothelial cell surface markers. Since the expression of the immortalizing genes was expected to strongly influence the cellular characteristics fibroblastoid cells were reversibly immortalized by using a vector that allows conditional expression of the TAg. Under inducing conditions, these cells exhibited properties that were highly similar to the properties of constitutively immortalized cells. In the absence of TAg expression, cell proliferation stops. Cell growth is resumed when TAg expression is restored. Gene expression profiling indicates that TAg influences the expression levels of more than 1000 genes that are involved in diverse cellular processes. The data show that conditionally immortalized cell lines have several advantageous properties over constitutively immortalized cells.

Automatic Reduction of Artifacts in EEG-Signals

Electroencephalograms (EEG) are often contaminated with high amplitude artifacts limiting the usability of data. Methods that reduce these artifacts are often restricted to certain types of artifacts, require manual interaction or large training data sets. Within this paper we introduce a novel method, which is able to eliminate many different types of artifacts without manual intervention. The algorithm first decomposes the signal into different sub-band signals in order to isolate different types of artifacts into specific frequency bands. After signal decomposition with principal component analysis (PCA) an adaptive threshold is applied to eliminate components with high variance corresponding to the dominant artifact activity. Our results show that the algorithm is able to significantly reduce artifacts while preserving the EEG activity. Parameters for the algorithm do not have to be identified for every patient individually making the method a good candidate for preprocessing in automatic seizure detection and prediction algorithms.

Noninvasive determination of intraocular pressure (IOP) in nonsedated mice of 5 different inbred strains

BACKGROUND: Noninvasive intraocular pressure (IOP) measurement in mice is critically important for understanding the pathophysiology of glaucoma. Rebound tonometry is one of the methods that can be used for obtaining such measurements. We evaluated the ability of the rebound tonometer (RT) to determine IOP differences among various mouse strains and whether differences in corneal thickness may affect IOP measurements in these animals. MATERIALS AND METHODS: Five different commonly used mouse strains (BALB/C, CBA/CAHN, AKR/J, CBA/J, and 129P3/J) were used. IOP was measured in eyes from 12 nonsedated animals (6 male and 6 female) from each strain at 2 to 3 months of age using the RT. IOPs were measured in all animals, on 2 different days between 10 AM and 12 PM. Subsequently, a number of eyes from each strain were cannulated to provide a calibration curve specific for that strain. Tonometer readings for all strains were converted to apparent IOP values using the calibration data obtained from the calibration curve of the respective strain. For comparison purposes, IOP values were also obtained using the C57BL/6 calibration data previously reported. IOP for the 5 strains, male and female animals, and the different occasion of measurement were compared using repeat measures analysis of variance. The central corneal thickness (CCT) of another group of 8 male animals from each of the 5 strains was also measured using an optical low coherence reflectometry (OLCR) pachymeter modified for use with mice. CCT values were correlated to mean IOPs of male animals and to the slopes and intercept of individual strain calibration curves. RESULTS: Noninvasive IOP measurements confirm that the BALB/C strain has lower and the CBA/CAHN has higher relative IOPs than other mouse strains while the AKR/J, the CBA/J, and the 129P3/J strains have intermediate IOPs. There is a very good correlation of apparent IOP values obtained by RT with previously reported true IOPs obtained by cannulation. There was a small but statistically significant difference in IOP between male and female animals in 2 strains (129P3/J and AKR/J) with female mice having higher relative IOPs. No correlation between CCT and IOP was detected. CCT did not correlate with any of the constants describing the calibration curves in the various strains. CONCLUSIONS: Noninvasive IOP measurement in mice using the RT can be used to help elucidate IOP phenotype, after prior calibration of the tonometer. CCT has no effect on mouse IOP measurements using the RT.