BedMachine v3: Complete Bed Topography and Ocean Bathymetry Mapping of Greenland From Multibeam Echo Sounding Combined With Mass Conservation.

Greenland's bed topography is a primary control on ice flow, grounding line migration, calving dynamics, and subglacial drainage. Moreover, fjord bathymetry regulates the penetration of warm Atlantic water (AW) that rapidly melts and undercuts Greenland's marine-terminating glaciers. Here we present a new compilation of Greenland bed topography that assimilates seafloor bathymetry and ice thickness data through a mass conservation approach. A new 150 m horizontal resolution bed topography/bathymetric map of Greenland is constructed with seamless transitions at the ice/ocean interface, yielding major improvements over previous data sets, particularly in the marine-terminating sectors of northwest and southeast Greenland. Our map reveals that the total sea level potential of the Greenland ice sheet is 7.42 ± 0.05 m, which is 7 cm greater than previous estimates. Furthermore, it explains recent calving front response of numerous outlet glaciers and reveals new pathways by which AW can access glaciers with marine-based basins, thereby highlighting sectors of Greenland that are most vulnerable to future oceanic forcing.

Lyophilized Clostridium perfringens 3 alpha- and Clostridium bifermentans 7 alpha-hydroxysteroid dehydrogenases: two new stable enzyme preparations for routine bile acid analysis.

Preparations of 3 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.50) from Clostridium perfringens were successfully lyophilized into a stable powder form. Purification of the enzyme was achieved using triazine dye affinity chromatography. C. perfringens 3 alpha-hydroxysteroid dehydrogenase was purified 24-fold using Reactive Red 120 (Procion Red) -cross-linked agarose (70% yield). Quantitative measurement of bile acids with the purified enzymes, 3 alpha-hydroxysteroid dehydrogenase and 7 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.159) from Clostridium bifermentans (strain F-6), was achieved spectrophotometrically. Standard curves with chenodeoxycholic acid (CDC) and cholic acid were linear within a concentration range of 20-100 microM. Analysis of mixtures of ursodeoxycholic acid and CDC showed the additive nature of the 3 alpha-hydroxysteroid dehydrogenase and showed also that 7 alpha-hydroxyl groups were independently quantified by the 7 alpha-hydroxysteroid dehydrogenase. Bile acids in Folch extracts of human bile samples were measured using purified preparations of Pseudomonas testosteroni 3 alpha-hydroxysteroid dehydrogenase, C. perfringens 3 alpha-hydroxysteroid dehydrogenase, Escherichia coli 7 alpha-hydroxysteroid dehydrogenase and C. bifermentans (strain F-6) 7 alpha-hydroxysteroid dehydrogenase. Statistical comparison validated the use of C. perfringens 3 alpha- and C. bifermentans 7 alpha-hydroxysteroid dehydrogenases for the quantification of bile acids in bile.

NAD- and NADP-dependent 7alpha-hydroxysteroid dehydrogenases from bacteroides fragilis.

Twenty strains of Bacteroides fragilis were screened for hydroxysteroid oxidoreductase activity in cell-free preparations. Eighteen strains were shown to contain NAD-dependent 7alpha-hydroxysteroid dehydrogenase. Sixteen of the strains containing the NAD-dependent enzyme also contained NADP-depedent 7alpha-hydroxysteroid dehydrogenase, but invariably in lesser amounts. A strain particulary rich in both 7alpha-hydroxysteroid dehydrogenase activities was selected for further study. Measurement of activity as a function of pH revealed a fairly sharp optimal activity range of 9.5--10.0 for the NAD-dependent enzyme and a broad flat optimal range of 7.0--9.0 for the NADP-dependent enzyme. Michaelis constants for trihydroxy-bile acids for the NAD-dependent enzyme were in the range of 0.32--0.34 mM, whereas dihydroxy-bile acids gave a Km of 0.1 mM. Thin-layer chromatography studies on the oxidation product of 3alpha, 7alpha-dihydroxy-5beta-cholanoic acid (chenodeoxycholic acid) by the dehydrogenase revealed a band corresponding to that of synthetic 3alpha-hydroxy, 7-keto-5beta-cholanoic acid. Similarly the oxidation product of chenodeoxycholic acid by both 7alpha-hydroxysteroid dehydrogenase and commercially available 3alpha-hy-droxysteroid dehydrogenase revealed a band corresponding to that of synthetic 3,7-diketo-5beta-cholanoic acid. Neither of these two oxidation products could be distinguished from those by the Escherichia coli dehydrogenase oxidation previously reported. Disc-gel electrophoresis of a cell-free lyophilized preparation indicated one active band for NAD-dependent activity of mobility similar to that for the NADP-dependent E. coli enzyme. The NADP-dependent dehydrogenase was unstable and rapidly lost activity after polyacylamide disc-gel electrophoresis, ultracentrifugation, freezing on refrigeration at 4 degrees C. No 3 alpha- or 12alpha-oriented oxidoreductase activity was demonstrated in any of the strains examined.

Bioavailability of four ursodeoxycholic acid preparations.

BACKGROUND: Ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. OBJECTIVES: The objective of this study was to compare the bioavailability of four commercially available ursodeoxycholic acid formulations in standardized doses. METHODS: Twenty-four healthy subjects were studied in groups of four, and received each of the different UDCA preparations in random order, with a 1-week washout or more in-between. Serum UDCA levels were determined for a 6-h period. The mean area under the curve (AUC), Cmax and Tmax were determined for each drug formulation, and the results compared. Dose proportionality was determined using the Canadian Ursofalk tablet using either 250 mg, 500 mg or 750 mg dosing. The intraparticipant variability was assessed by asking each participant to repeat the last drug that they took the second time, 1 week later. RESULTS: The mean AUC was 68.99 micromol/1.6 h-1 for the USA UDCA tablet, 59.34 micromol/1.6 h-1 for the Canadian UDCA tablet, 55.55 micromol/1.6 h-1 for Ursolvan capsules, and 46.66 micromol/1.6 h-1 for Actigall capsules. The mean Cmax values were 24.29, 17.85, 16.63 and 413.32 nmol/mL, respectively. The mean Tmax was 1.82, 2.3, 2.79 and 3.39 h, respectively. Linear aggression analysis assessing the direct proportionality of AUC on the dose for the Canadian UDCA tablet gave an estimate of 0.063 + 0.0164 (standard error, P-value=0.0117), e.g. if the dose increases from 250 mg to 500 mg, the serum ursodeoxycholic acid increases by 250 x 0.063=15.75. There was excellent reproducibility for the AUC for the North American tablets (0.97, 0.88) compared to the two capsules (0.32, 0.15). CONCLUSIONS: The significantly higher AUC and Cmax and shorter Tmax for the Canadian Ursofalk tablets compared to the UDCA capsule preparations supports better bioavailability.

Bile-acid metabolism and the liver.

Primary bile acids are exclusively synthesize, and all bile acids are conjugated, in the liver. When hepatic function is altered by disease, not surprisingly the bile-acid metabolism reflects this change. 1. In chronic liver disorders the glycine: taurine ratio of serum and bile is reduced. 2. In cases of relapsing acute hepatitis and relapsing chronic active hepatitis the serum bile acids are increased, providing an aid to early diagnosis. Their pattern often distinguishes chronic cholestatic conditions from Laennec's cirrhosis. 3. In chronic liver disease, the concentration of intraduodenal bile acids is reduced; when the reduction is severe, this probably accounts for co-existent steatorrhoea. 4. In Laennec's cirrhosis, both the synthesis and pool size of cholic acid are markedly depressed; in primary biliary cirrhosis, however, preliminary data indicate a decrease in the chenodeoxycholic acid component.

Behavior of 3alpha- and 7alpha-hydroxysteroid dehydrogenases on chenodeoxycholate substituted Sepharose.

Chenodeoxycholate (3alpha-, 7alpha-dihydroxy-5beta-cholanoate) was linked to Sepharose 4B by an ethylenediamine bridge. When 3alpha-hydroxysteroid dehydrogenase and 7alpha-hydroxysteroid dehydrogenase preparations were applied to a column of covalently linked chenodeoxycholate, both enzymes were retarded at pH 6.7; the 7alpha-OH oriented enzyme more than the 3alpha-OH enzyme. Approximately forty-fold purification of 7alpha-hydroxysteroid dehydrogenase was achieved in one step. Although no significant purification of 3alpha-hydroxysteroid dehydrogenase occurred, the background value in the fluorometric enzymatic estimation of bile acids by eluted 3alpha-hydroxysteroid dehydrogenase was markedly reduced. Molecular weight estimation by Sephadex G-200 gave the values of 47,000 for 3alpha-hydroxysteroid dehydrogenase and 105,000 for 7alpha-hydroxysteroid dehydrogenase.

Gastroesophageal reflux disease.

Chronic GERD is an unremitting, incurable disorder that recurs rapidly upon discontinuation of therapy. Primary complications of GERD include esophagitis, esophageal stricture and Barrett esophagus. Current therapy focuses on modifying risk factors, inhibiting the production of acid and enhancing esophageal gastric motility. In patients with uncomplicated heartburn, nondrug therapy should be the initial therapeutic approach, with patient education a major step in promoting lifestyle changes and improving the outcome. Maintenance therapy is central to the management of GERD. If symptoms persist to suggest complicated disease, further diagnostic tests (endoscopy) are indicated. H2 receptor antagonists usually resolve symptoms in 50% to 70% of patients, and PPIs in 74% to 96% of patients. Agents that improve esophageal motility, such as cisapride, may provide symptomatic relief of heartburn, but healing effects are inconsistent. In refractory disease, therapy is individualized to the patient, and may include combination therapy, more aggressive single line therapy or an appropriate surgical approach.

Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up.

BACKGROUND AND DESIGN: Methotrexate (MTX) hepatotoxicity in psoriatic patients is well recognized, but there are discrepancies in the reported incidence and associated risk factors. This retrospective study describes 104 Nova Scotian patients with psoriasis seen between 1979 and 1990. Patients received MTX over one to 11 years (mean 3.38), with baseline and annual follow-up liver biopsies. Clinical data were obtained by chart review. Statistical analysis evaluated the risks associated with obesity, diabetes, alcohol consumption and duration of therapy, with the histological grade of liver biopsies. RESULTS: Of the 104 patients, 35 were obese, 10 were diabetic and 37 occasionally consumed alcohol. At the end of the study, 21 patients had developed severe hepatic fibrosis (grade IIIB), and three developed liver cirrhosis (grade IV). Significant risk of severe hepatotoxicity is related to diabetes (P = 0.02) but not to obesity (P = 0.12) or alcohol consumption (P = 0.12). All patients with cirrhosis took MTX for two years in standard doses of 20 to 25 mg/week. CONCLUSIONS: In this first Canadian study evaluating MTX hepatotoxicity in psoriatics, the incidence of severe hepatotoxicity is high: 23.1% (24 of 104 patients). This study shows that diabetic patients are particularly at increased risk of MTX hepatotoxicity. Occasional alcohol consumption is not associated with increased risk. Three patients who developed cirrhosis over two years of standard MTX therapy may represent a subset of psoriatics with increased hepatic susceptibility to MTX. Another three patients whose severe hepatic fibrosis had regressed upon discontinuation of MTX, but who developed accelerated recurrence of the severe hepatic fibrosis upon resumption of MTX therapy, also suggest the possibility of unusual sensitivity to the drug. These cases emphasize the need for continuing surveillance, with regular liver biopsies, of psoriatic patients on MTX.

The costs of crime and the benefits of substance abuse treatment for pregnant women.

Although many pregnant, drug-dependent women report extensive criminal justice involvement, few studies have examined reductions in crime as an outcome of substance abuse treatment programs for pregnant women. This is unfortunate, because maternal criminal involvement can have serious health and cost implications for the unborn child, the mother and society. Using the Addiction Severity Index, differences in pre- and posttreatment criminal involvement were measured for a sample of 439 pregnant women who entered publicly funded treatment programs in Massachusetts between 1992 and 1997. Accepted cost of illness methods were supplemented with information from the Bureau of Justice Statistics to estimate the costs and benefits of five treatment modalities: detoxification only (used as a minimal treatment comparison group), methadone only, residential only, outpatient only, and residential/outpatient combined. Projected to a year, the net benefits (avoided costs of crime net of treatment costs) ranged from US$32,772 for residential only to US$3,072 for detoxification. Although all five modalities paid for themselves by reducing criminal activities, multivariate regressions controlling for baseline differences between the groups showed that reductions in crime and related costs were significantly greater for women in the two residential programs. The study provides economic justification for the continuation and possible expansion of residential substance abuse treatment programs for criminally involved pregnant women.

Immediate and long-term management of gunshot wounds to the lower face.

The steadily increasing level of urban violence and attempted suicides in the recent past has resulted in large numbers of gunshot injuries to the face from small-caliber weapons. Our experience with 35 consecutive cases of civilian gunshot wounds involving primarily the lower face is presented. Initial management included securing of the airway, control of bleeding, and treatment of coexisting injuries. After clinical and radiologic evaluation and conservative debridement of all devitalized tissues, the mandibular fractures were reduced and stabilized appropriately. Large bony defects were treated by stabilization of the mandibular segments followed by secondary bone grafting. Intraoral soft tissues were then repaired with local mucosal flaps or tongue flaps when necessary. Finally, the soft tissues were repaired by primary closure or local flaps. Distant flaps were used only as a secondary procedure. Our results are presented, the differences between civilian and military injuries are discussed, and the principles of gunshot ballistics are described. We conclude that most of these wounds can be treated in a relatively conservative manner immediately after the injury with good functional and cosmetic results.

Dissecting cellulitis of the scalp.

Dissecting cellulitis of the scalp or perifolliculitis capitis abscedens et suffodiens is a rare, chronic, progressive, suppurative disease of the scalp of unknown etiology. It is characterized by painful nodules, purulent drainage, burrowing interconnecting abscesses, and cicatricial alopecia. The pathogenesis is unknown, although it is probably related to follicular occlusion, secondary infection, and deep inflammation. Black men in their second to fourth decade are predominantly affected. Treatment varies from systemic antibiotics to incision and drainage, x-ray epilation of the affected areas, systemic steroid administration, and surgical excision. Our experience with four patients with extensive scalp disease is presented. Wide excision of the affected areas and splitthickness skin graft are favored as our treatment of choice.

The impact of substance abuse treatment modality on birth weight and health care expenditures.

During the 1990s, substance abuse treatment programs were developed for pregnant women to help improve infant birth outcomes, reduce maternal drug dependency and promote positive lifestyle changes. This study compared the relative impact of five treatment modalities--residential, outpatient, residential/outpatient, methadone and detoxification-only--on infant birth weight and perinatal health care expenditures for a sample of 445 Medicaid-eligible pregnant women who received treatment in Massachusetts between 1992 and 1997. Costs and outcomes were measured using the Addiction Severity Index and data from birth certificates, substance abuse treatment records and Medicaid claims. Multiple regression was used to control for intake differences between the groups. Results showed a near linear relationship between birth weight and amount of treatment received. Women who received the most treatment (the residential/outpatient group) delivered infants who were 190 grams heavier than those who received the least treatment (the detoxification-only group) for an additional cost of $17,211. Outpatient programs were the most cost-effective option, increasing birth weight by 139 grams over detoxification-only for an investment of only $1,788 in additional health care and treatment costs. A second regression using five intermediate treatment outcomes--prenatal care, weight gain, relapse, tobacco use and infection--suggested that increases in birth weight were due primarily to improved nutrition and reduced drug use, behaviors which are perhaps more easily influenced in residential settings.

Role of rectal formulations: suppositories.

Mesalazine (5-aminosalicylic acid) suppositories are safe, effective, well tolerated, and well retained in patients with active distal proctitis. The best results are seen in patients with idiopathic ulcerative proctitis. Approximately 85% of these patients are healed within 4 weeks and virtually 100% by 10 weeks, with mucosal healing and complete loss of symptoms. Suppositories cover the last 20 cm of the rectum, as shown by technetium labelling. Maintenance therapy using suppositories alone--in doses varying from 500 mg every second bedtime to 1000 mg per day in divided doses--is at least as effective as oral sulphasalazine. Mesalazine suppositories are also useful in treating patients with Crohn's disease affecting the rectum, although the response rate is slower and healing is incomplete in half the patients treated. In the rare solitary rectal ulcer syndrome, mesalazine suppositories may be as efficacious as mesalazine enemas. Patient compliance and dramatic response even when conventional therapy has failed make an excellent case for mesalazine suppositories being the treatment of choice for distal ulcerative proctocolitis.