Ludwig II, King of Bavaria: a royal medical history.

OBJECTIVE: The case of Ludwig II, King of Bavaria, had soon become synonymous with paranoia, after he had drowned at the age of 40 together with the neuropsychiatrist Gudden. METHOD: We were granted access to the Secret Archive of the House of Wittelsbach to study documents on Ludwig's medical history. RESULTS: The documents underlying Gudden's expert opinion which led to Ludwig being deposed would be insufficient for a diagnosis of schizophrenia according to contemporary standards. The autopsy revealed prominent prefrontal brain atrophy. CONCLUSION: The evidence is compatible with a diagnosis of schizotypal personality and suspected frontotemporal degeneration.

[Ludwig II of Bavaria: schizotypal personality disorder and frontotemporal dementia?]. / Ludwig II. von Bayern--schizotype Persönlichkeit und frontotemporale Degeneration?

Ludwig 2nd, dream-king of Bavaria, has been the subject of medical speculation even during his life and he still is today. Documents from the Secret Archive of the Bavarian State and more widely available information do not support a diagnosis of schizophrenia, but correspond with contemporary criteria for a schizotypal personality disorder. Ludwig's behavioural deterioration during the last months of his life and autopsy findings may indicate incipient frontotemporal degeneration.

Influence of tissue origins and external microenvironment on porcine foetal fibroblast growth, proliferative life span and genome stability.

One of the challenges of manipulating genes in primary cells is that the cells have a finite proliferation capacity. This, combined with the lower gene targeting efficiency of somatic cells, makes identification of targeted clones very difficult. The objective of this study was to establish a system that allows porcine foetal fibroblasts to reach their maximal proliferation capacity in vitro. The influence of fibroblast origin, stage of foetal development, cell seeding densities and concentration of foetal bovine serum (FBS) on the population doublings, the percentage of beta-galactosidase-activity-positive cells and the genome stability of foetal fibroblasts during in vitro culture was investigated. It was found that porcine foetal fibroblasts could be cultured for over 80 population doublings in the appropriate culture system. Fibroblasts from earlier stages of foetal development were better candidate cells than those from the later stages. Cells from the heart were more actively proliferative and more resistant to replicative senescence than those from the liver. Compared to 10% FBS content, 15% FBS provided better homeostatic support, not only to proliferative performance, but also in maintaining a normal karyotype. In addition, the proliferative life span of porcine foetal fibroblasts is also dependent on seeding density of the culture.

Determination of true digestive utilization of phosphorus and the endogenous phosphorus outputs associated with soybean meal for growing pigs.

The objectives of this study were to determine true P digestibility, the gastrointestinal endogenous P outputs associated with soybean meal (SBM), and the role of the large intestine in P digestion in growing pigs. Four Yorkshire barrows, with average initial and final BW of 40 and 58 kg, were fitted with a simple T-cannula at the distal ileum and fed four diets according to a 4 x 4 Latin square design. The diets were cornstarch-based and contained four levels of P (0.098, 0.196, 0.293, and 0.391% on a DM basis) from solvent-extracted conventional SBM. Chromic oxide (3.5 g/kg of diet, as-fed basis) was included as a digestibility marker. Each experimental period consisted of 8 d with a 4-d adaptation period and a 4-d collection of representative ileal digesta (2 d) and fecal (2 d) samples. True ileal and fecal P digestibility values and the ileal and fecal endogenous P outputs associated with SBM were determined by the regression analysis technique. There were no differences (P > 0.05) in true P digestibility values (ileal, 59.0 +/- 8.3 vs. fecal, 51.3 +/- 7.9%, n = 16) and endogenous P outputs (ileal, 0.59 +/- 0.18 vs. fecal, 0.45 +/- 0.21 g/kg of DMI, n = 16) between the ileal and the fecal levels. The endogenous fecal P loss accounted for 8.1 and 17.6% of the NRC (1998) recommended total and available P requirements in growing pigs, respectively. In conclusion, approximately 51% of the total P in conventional SBM is digested in growing pigs. The large intestine does not play an important role in the digestion of P associated with SBM in the growing pig. The fecal loss of the gastrointestinal endogenous P is an important route of P excretion in the growing pig.

Enhanced conditioned inhibitory avoidance by a combined extract of Zingiber officinale and Ginkgo biloba.

Previous work has shown that intragastric administration of Zingicomb, a preparation consisting of Zingiber officinale and Ginkgo biloba extracts, has anxiolytic-like properties. The aim of the present study was to assess the effects of acute treatment with this preparation on inhibitory avoidance learning. The influence of pre-trial administered Zingicomb (ZC) on inhibitory avoidance conditioning was investigated in adult male Wistar rats, with a one-trial step-through avoidance task. The animals were treated intragastrically with either vehicle, 0.5, 1, 10 or 100 mg/kg ZC 60 min prior to the acquisition trial. When tested 24 h after training, rats which had received 10 mg/kg ZC exhibited significantly longer step-through latencies than vehicle treated animals. This result, thus, demonstrates the beneficial effects of Zingicomb on conditioned inhibitory avoidance. Unlike conventional anxiolytic drugs, such as the benzodiazepines, which tend to have amnesic properties, this phytopharmacon is a potent anxiolytic agent which, additionally, can facilitate performance on a learning task, indicating promising clinical applications.

Enhanced maze performance and reduced oxidative stress by combined extracts of zingiber officinale and ginkgo biloba in the aged rat.

Here we assessed the effects of i.g. administration of Zingicomb (ZC), a mixture of zingiber officinale and ginkgo biloba extracts, on learning and memory, and on indicators of oxidative stress in aged rats. Effects of ZC (1 and 10 mg/kg) were investigated in 22-24 months old Wistar rats using the Morris water maze, in which they show deficient performance as compared to 3 months old rats in the undrugged state (days 1 and 2). Treatment was administered on days 3 and 4 of training, then over 7 days with training discontinued, and again on days 5 and 6 when training was resumed. Thereafter chronic treatment was maintained over 5 months. 1 mg/kg ZC improved escape learning in the water maze. The two capital indicators of oxidative stress in brain homogenates, the amount of oxidized proteins (assessed as carbonyl group containing proteins) and lipid peroxidation, were significantly reduced in ZC treated animals. Thus, ZC, which had previously been shown to improve inhibitory avoidance learning and to have anxiolytic properties in adult animals, might also facilitate spatial learning in aged animals, and reduces indices of oxidative stress in brain tissue after chronic treatment.

Novel methodology allows simultaneous measurement of true phosphorus digestibility and the gastrointestinal endogenous phosphorus outputs in studies with pigs.

Methodology was developed for measuring the gastrointestinal endogenous phosphorus (P) outputs and true P digestibility values in studies with piglets. Four barrows, average initial body weight 6.8 kg, were fitted with a simple T-cannula at the distal ileum and fed four diets according to a 4 x 4 Latin square design. Four cornstarch-based diets containing four levels of P (1.1, 2.1, 3.2 and 4.3 g/kg diet) on a dry matter (DM) basis were formulated from soybean meal (SBM). Each experimental period comprised 8 d with a 4-d adaptation and 4-d collection of ileal digesta and feces. The apparent ileal and fecal P digestibility values in SBM were affected (P < 0.05) by P levels in the assay diets. The ileal and fecal P digestibility values increased from -24.8 to 37.1% and from 18.8 to 42.5%, respectively, as P contents increased from 1.1 to 4.3 g/kg DM diet. Linear relationships (P < 0.05), expressed as g/kg DM diet intake, between ileal and fecal outputs and dietary inputs of P, suggested that the endogenous P outputs can be determined by linear regression analysis. The endogenous P output was higher (P < 0.05) in ileal digesta than in feces (0.86 +/- 0.09 vs. 0.31 +/- 0.06 g/kg DM diet intake). There was no difference (P > 0.05) between the true ileal (50.7 +/- 7.1%) and fecal (48.5 +/- 5.4%) P digestibility values in SBM. These results suggest that differences in P contents between assay diets are primarily responsible for the large variability in apparent P digestibility values reported within the same ingredient. Apparent digestibility values underestimate the true digestive utilization of P by approximately 25%. True rather than apparent P digestibility values should be determined and used in diet formulation for pigs. In addition, this study shows that the gastrointestinal endogenous P output is important in whole-body P requirement and homeostasis.

Pigs expressing salivary phytase produce low-phosphorus manure.

To address the problem of manure-based environmental pollution in the pork industry, we have developed the phytase transgenic pig. The saliva of these pigs contains the enzyme phytase, which allows the pigs to digest the phosphorus in phytate, the most abundant source of phosphorus in the pig diet. Without this enzyme, phytate phosphorus passes undigested into manure to become the single most important manure pollutant of pork production. We show here that salivary phytase provides essentially complete digestion of dietary phytate phosphorus, relieves the requirement for inorganic phosphate supplements, and reduces fecal phosphorus output by up to 75%. These pigs offer a unique biological approach to the management of phosphorus nutrition and environmental pollution in the pork industry.

Aortic root replacement versus aortic valve replacement: a case-match study.

BACKGROUND: There is increasing evidence that patients with aortic valve disease and dilatation of the ascending aorta are at risk for later dissection or rupture of the aortic wall when the dilated ascending aorta is not replaced or reinforced at the time of aortic valve replacement. In order to find out whether the more complex surgical procedure of aortic root replacement carries a higher early or late postoperative risk than isolated aortic valve replacement, we conducted a matched-pair study with patients of both groups. METHODS: Between June 1993 and August 1998, 100 consecutive patients with aortic valve disease and ectasia/aneurysm of the ascending aorta underwent replacement of the aortic valve and the ascending aorta with a CarboSeal composite graft (CarboSeal; Sulzer Carbo-Medics Inc, Austin, TX). Identical bileaflet valve prostheses (CarboMedics; Sulzer CarboMedics Inc, Austin, TX) were implanted during the same time period in 928 patients for aortic valve disease. On the basis of various preoperative clinical variables 100 patients with aortic valve replacement were matched to the 100 patients with replacement of the aortic root. The duration of follow-up for both groups was similar with 37 + 17 months (range, 9 to 70) for the CarboSeal group and 38 + 14 months (range, 13 to 65) for the CarboMedics group. Survival and morbidity were calculated by Kaplan-Meier analysis and risk-adjusted mortality was evaluated by multivariate analysis in a Cox regression model. RESULTS: The early postoperative mortality of 1% in the CarboSeal group and 4% in the CarboMedics group was insignificantly different. Although the overall survival rate at 5 years was lower (60.7% vs 86.3%; p = 0.13) in the CarboSeal group, the freedom from cardiac mortality and valve-related morbidity was similar in the two groups. CONCLUSIONS: Replacement of the ascending aorta and aortic valve can be performed with similar operative risk, valve-related morbidity, and late cardiac mortality as isolated aortic valve replacement.

Intermediate-term results with 1,019 carbomedics aortic valves.

BACKGROUND: A retrospective study was conducted to evaluate the intermediate-term outcome in patients with the Carbomedics aortic valve prosthesis. METHODS: The study included 1,019 primary valve replacements between 1989 and 1997. Seventy-two percent of patients were men; mean (standard deviation) age was 61 (10) years. The preoperative New York Heart Association functional class was III or IV in 70% of patients. Follow-up at 9 years was 99.6% complete, comprising 2,730 patient-years (mean, 2.7 years). RESULTS: Patient survival, including operative deaths, was 80% at 7 years. The linearized death rate was 2.9%/year. Statistically significant risk factors for mortality were diabetes, pure valve insufficiency, advanced age at operation, and advanced preoperative functional class. Linearized rates were thrombosis, 0.1%/year; thromboembolism, 1.0%/year; hemorrhage, 1.7%/year; endocarditis, 0.1%/year; paravalvular leak, 0.1%/year; reoperation, 0.1%/year; and all events, 3.0%/year. The 7-year estimates of freedom from complications were thrombosis, 99%; thromboembolism, 93%; hemorrhage, 89%; endocarditis, 99%; paravalvular leak, 99.7%; reoperation, 99%; and all events, 82%. No structural valve failure was observed. CONCLUSIONS: The low incidence of valve-related complications favors the continued use of the Carbomedics valve in the aortic position.

A prospective randomized multicenter clinical evaluation of an anterior cervical fusion cage.

STUDY DESIGN: A prospective, concurrently controlled, randomized, multicenter trial of an anterior Bagby and Kuslich cervical fusion cage (BAK/C; Sulzer Spine-Tech, Minneapolis, MN) for treatment of degenerative disc disease of the cervical spine. OBJECTIVES: To report clinical results with maximum 24-month follow-up of fusions performed with the BAK/C fusion cage. SUMMARY OF BACKGROUND DATA: Threaded lumbar cages have been used during the past decade as a safe and effective surgical solution for chronic disabling low back pain. Threaded cages have now been developed for use in anterior cervical interbody fusions to obviate the need for allografts or autogenous bone grafting procedures while providing initial stability during the fusion process. METHODS: Patients with symptomatic cervical discogenic radiculopathy were treated with either anterior cervical discectomy with uninstrumented bone-only fusion (ACDF) or BAK/C fusion cage(s). Independent radiographic assessment of fusion was made and patient-based outcome was assessed by visual analog pain scale and a Short Form (SF)-36 Health Status Questionnaire. RESULTS: Data analysis included 344 patients at 1 year and 180 at 2 years. When the two cage groups (hydroxya, patite-coated or noncoated) were compared with the ACDF group, similar outcomes were noted for duration of surgery, hospital stay, improvements in neck pain and radicular pain in the affected limb, improvements in the SF-36 Physical Component subscale and Mental Component subscale, and the patients' perception of overall surgical outcome. Symptom improvements were maintained at 2 years. A greater percentage of patients with ACDF needed an iliac crest bone harvest than did BAK/C patients (67% vs.- 3%). Successful fusion for one-level procedures at 12 months was 97.9% for the BAK/C groups and 89.7% for the ACDF group (P < 0.05). The complication rate for the ACDF group was 20.4% compared with an overall complication rate of 11.8% with BAK/C. There was no difference in complications that necessitated a second operative procedure. CONCLUSIONS: These results demonstrate that outcomes after a cervical fusion procedure with a threaded cage are the same as those of a conventional uninstrumented bone-only anterior discectomy and fusion with a low risk of complications and rare need for autogenous bone graft harvest.

A randomized prospective study of an anterior cervical interbody fusion device with a minimum of 2 years of follow-up results.

OBJECT: Despite variations in technique, inherent problems persist with current approaches to anterior cervical fusion. This study was performed to determine whether anterior cervical fusion performed using an investigational device was safe and effective in the treatment of degenerative cervical disc disorders and whether this device offered advantages over current techniques. METHODS: Fifty-four patients with radiculopathy with or without mild myelopathy due to one- or two-level cervical degenerative disc disease were randomized as part of a Food and Drug Administration device study. Following microsurgical discectomy, the control group was treated with iliac crest graft fusion; the experimental study group underwent insertion of an interspace cage and placement of a local autograft. All patients received postoperative follow-up care for at least 2 years. Good or excellent results were found in approximately 97% of the experimental group and 88% of the control group. A solid fusion was achieved in all patients who underwent one-level cage placement, and a solid fusion at one or both levels was achieved in over 90% of both groups. Chronic donor site pain was reported by 31% of the control group. CONCLUSIONS: In this study, the use of an interbody fusion cage avoided donor site morbidity and placement of autograft achieved a high rate of good or excellent results. Interbody fusion cages appear safe and effective, and their use helps to avoid some of the inherent problems in performing current anterior cervical fusion techniques.

Replacement of the aortic valve and ascending aorta with a valved stentless composite graft: technical considerations and early clinical results.

BACKGROUND: Replacement of the aortic valve and the ascending aorta with a conduit consisting of a mechanical valve and a Dacron tube has become a fairly common procedure. Commercially available conduits employing xenografts are rarely used for the same purpose, because if a reoperation becomes necessary due to degeneration of the valve prosthesis, usually the entire conduit must be replaced. A composite graft with a stentless valve, such as we describe in this article, avoids this problem, because in case of reoperation only the valve cusps need to be resected and the tube graft may be left in place. METHODS: Surgical technique of replacement of the aortic valve and the ascending aorta with a stentless composite graft and early results of the procedure are presented. RESULTS: Hemodynamics of the graft soon after surgery were excellent, with an average systolic gradient of 8 mm Hg and no regurgitation across the valve. There were two reoperations for bleeding in the early postoperative period. CONCLUSIONS: The stentless composite graft we describe provides excellent hemodynamics, has no need for anticoagulation, and is expected to offer a benefit in case of reoperation.

First clinical experience with a mechanical valve with silver coating.

BACKGROUND AND AIM OF THE STUDY: The interface between the annulus and sewing cuff is the infectious center of prosthetic valve endocarditis (PVE). To decrease the incidence of PVE, the sewing cuff of the St. Jude Medical (SJM) mechanical heart valve was permanently coated with elemental silver (Silzone coating). In vitro data have supported the antimicrobial efficacy of this coating. METHODS: To study any adverse effects of the silver coating in humans, serum silver levels were determined (by graphite furnace atomic absorption spectrometry) before (baseline) and at five intervals after operation: day 1, day 3, discharge, one month, and two months. Between January and August 1997, 38 patients (71% males) underwent surgical implant of a SJM Masters Series valve with Silzone coating for the aortic valve (n = 29), mitral valve (n = 6), or both valves (n = 3). Five patients (13%) underwent concomitant procedures. Two patients (5%) presented with native active valve endocarditis. RESULTS: There was no hospital mortality or valve-related hospital morbidity. Blood silver concentrations peaked shortly after surgery and then decreased during the postoperative period. Average levels were consistently below 4 parts per billion (ppb). Levels below 10 ppb are considered normal. Follow up was 95% complete. There were no recurrent or new cases of endocarditis. CONCLUSION: These clinical data indicate that the SJM Masters Series valve with Silzone coating performs well. No adverse effects of the silver coating could be detected, and there were no valve-related complications.

Circadian variation of portal, arterial and venous blood levels of melatonin in pigs and its relationship to food intake and sleep.

Circadian levels of melatonin were determined in the hepatic portal vein, cranial vena cava, and the lower aorta of ten juvenile pigs. Blood was sampled every hour for a total of 24 hr via temporary cannulas introduced into blood vessels under anesthesia. No peak levels of melatonin were found in the mid-scotophase, but hepatic portal concentrations peaked at 06.00 hr. Overall levels of melatonin were highest in the hepatic portal vein (range 35-65 pg/mL), followed by an artery (range 30-55 pg/mL) and the vena cava (range 25-35 pg/mL). Levels of melatonin exhibit strong variation between individual pigs, but generally the average levels from all three sources follow each other's time course. However, on occasion, melatonin levels in the hepatic portal vein varied independently from the levels in the vena cava. Large portal peaks were usually preceded by a feeding period and were associated with a subsequent period of sleep. The data indicate that: 1) there is no clear circadian rhythm of melatonin in the peripheral blood of pigs, 2) relatively little melatonin is metabolized during the first liver passage, 3) food intake may elevate melatonin levels in the hepatic portal vein, and 4) increased levels of melatonin originated in the gastrointestinal tract may induce sleep.

Melatonin concentrations in the luminal fluid, mucosa, and muscularis of the bovine and porcine gastrointestinal tract.

Melatonin concentrations were measured in serum, luminal fluid, and tissues of the mucosa and muscularis of the entire bovine and porcine gastrointestinal tract (GIT). In both species, GIT levels profoundly exceeded serum levels. In pigs, melatonin was lowest in the luminal fluid and highest in the mucosa. No difference was found in various layers of bovine GIT. Compared to pigs, cows had higher melatonin levels in the stomach and ileum, but lower in the cecum and colon. There was no difference in melatonin levels between anterior and posterior segments of bovine GIT, whereas pigs exhibited several fold higher concentration of melatonin in the posterior segment (cecum and colon). Conversely, melatonin values in the anterior segment were significantly higher in cows, but in the posterior segments porcine values were higher. In cows, concentrations in the mucosa correlated with levels in the muscularis. Melatonin levels in the mucosa and muscularis were higher in the rumen and reticulum than in the omasum and abomasum. The species-specific levels and a distinct distribution of melatonin in the layers of the digestive tube indicates that this indole may be involved in the modulation of gastrointestinal function of monogastric as well as polygastric ungulates, albeit in a different capacity.

Papillary muscle shortening for mitral valve reconstruction in patients with ischaemic mitral insufficiency.

AIMS: To evaluate the feasibility of papillary muscle shortening in a specific group of high risk patients with ischaemic mitral regurgitation undergoing mitral valve reconstruction. BACKGROUND: From January 1996 to December 1997, 712 (10.1%) out of a total of 7042 open heart patients underwent mitral valve surgery in our hospital. Mitral valve reconstruction was performed in 408 of these patients (57.3%) and valve replacement had to be performed in 304 patients (42.7%). METHODS: A specific technique of papillary muscle reconstruction was performed in 32 patients undergoing valve reconstruction (7.8%). These cases had degenerated and had developed fibrotic elongated papillary muscles, which resulted in prolapses of one or more parts of the mitral valve leaflets. The aetiology in this group of patients was ischaemic, requiring concomitant myocardial revascularization in 28 patients (87.5%) with a mean of 2.7 grafts/patient. All patients underwent papillary muscle shortening using a pericardium pledget-reinforced Polytetrafluoroethylene suture and annuloplasty with a Carpentier-Edwards Physio Annuloplasty Ring. Of these 32 patients, 17 (53.1%) were male, the mean age was 67.1+/-9.7 years (range 41 to 81 years) and all but one were in pre-operative NYHA class III or IV. RESULTS: There were two hospital deaths (6.2%). Postoperative Doppler echocardiography indicated satisfactory mitral valve function in all patients. Within the short mean follow-up period of 9.6+/-5.4 months (3 to 26 months) there was one non-cardiac-related death (3.1%). There was no need for reoperation, and no cases of thromboembolic and bleeding complications in the postoperative period. All patients were in NYHA functional class I or II at the time of follow-up. CONCLUSION: Our results indicate that mitral valve repair is a safe treatment for this group of high risk patients, and that papillary muscle shortening is a valuable tool in these patients with ischaemic mitral regurgitation undergoing surgery.

[Isolated prolapse of the posterior leaflet of the mitral valve. Results of reconstructive surgery]. / Prolapsus isolé du feuillet postérieur de la valve mitrale. Résultats de la chirurgie reconstructrice.

Out of 522 patients undergoing mitral valve reconstruction for mitral regurgitation between 1988 and June 1994, the authors studied 159 cases of isolated mitral regurgitation by prolapse of the posterior mitral leaflet. There were 98 men (62%) and 61 women (38%), with an average age of 58.4 +/- 10.4 years. The functional class and ejection fraction were 2.8 +/- 0.11 and 0.66 +/- 0.2 respectively. In 155 patients, surgery consisted in quadrangular resection of the prolapsed tissue, followed in 83 cases by sliding posterior valvuloplasty and in 72 cases by plicature of the annulus. In 4 cases, the prolapse was treated by implantation of artificial chordae tendinae. A Carpentier-Edwards ring was inserted in all cases. There were no hospital deaths. Echocardiography was performed before discharge from hospital and showed satisfactory mitral valve function in 98% of cases: slight systolic anterior motion (SAM) was observed in one case. All patients were followed up for an average of 3.67 +/- 0.10 years. At six years, survival was 93 +/- 7%; moreover, 93 +/- 7% and 97 +/- 3% of patients had no thromboembolic or haemorrhagic complications. Six patients were reoperated, three of them in the first year of follow-up. At six years, 95 +/- 5% of patients were free of reoperation and 81 +/- 11% were free of all complications. The authors conclude that the excellent medium term survival and the low rate of complications are evidence in favour of conservative surgery for treatment of mitral regurgitation due to prolapse of the posterior mitral leaflet.