Adult phenylketonuria outcome and management.

The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase. Recent, partly double blind studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted. Late detected PKU patients (up to 4-6 years of age) benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may benefit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. In early and well treated patients a number of studies have demonstrated that cognitive and neurosychologic tests are different from controls. In addition there is evidence that patients with higher blood phenylalanine (phe) levels demonstrate more often psychiatric symptoms like depression and anxiety. Medical problems are more often observed: there are certain risks as impaired growth, decreased bone mineral density and nutrional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe (mean blood phenylalanine >600-900 µmol/L) on cognitive and neuropsychological functions and psychiatric symptoms. Further studies should consider the role of blood phe exposure for brain development in childhood and for brain function in all ages. Besides mean blood phe, fluctuation of blood phe over time is important. Fluctuation of blood phe is decreased by sapropterin treatment in responsive patients which would on the long term may have positive effects on cognitive outcome. Further studies also should include adult PKU patients.

Vagus nerve stimulation in refractory epilepsy: effects on pro- and anti-inflammatory cytokines in peripheral blood.

OBJECTIVE: The vagus nerve has important immunological functions that may be relevant for its anticonvulsive action. We postulate that this anticonvulsive action is activated by a shift in the immune system resulting in a reduction of neurotoxic and an increase of neuroprotective tryptophan metabolites. METHODS: Eleven patients with refractory epilepsy and 11 controls matched for age and gender were included in this study. The primary outcome measure was a 50% seizure reduction. Other variables were pro-inflammatory cytokines IL-6 and TNF-α, anti-inflammatory cytokine IL-10, cortisol, and the tryptophan metabolites 3-hydroxykynurenine (3-OH-KYN), kynurenic acid (KYNA), kynurenine, serotonin (5-HT) and 5-hydroxyindol acetic acid (5-HIAA). Blood samples were scheduled during baseline, and in week 28 of add-on treatment. RESULTS: IL-6 levels were higher in the responders than in the control group, and decreased after vagus nerve stimulation (VNS), whereas IL-10 was low and increased after VNS. In nonresponders, VNS resulted in an increase of IL-6 plasma levels and in a decrease of IL-10. Cortisol concentrations are higher in the epilepsy group than in the control group. After VNS, these concentrations decreased. The concentrations of the tryptophan metabolites were lower in the epilepsy group than in the control group. The KYNA ratios are defined as the ratio of neuroprotective KYNA versus neurotoxic 3-OH-KYN and KYNA versus neurotoxic kynurenine: these ratios were lower in epilepsy patients than in controls, and they both moderately increased after VNS. CONCLUSION: The outcome of this preliminary study indicates that VNS causes a rebalancing of the immune system. This results in: (1) a reduction of neurotoxic and an increase of neuroprotective kynurenine metabolites and (2) in the normalization of cortisol levels.

[Helping antibodies. Targeted antithrombotic and fibrinolytic therapy]. / Antikörper als Helfer. Zielgerichtete antithrombotische und fibrinolytische Therapie.

The development of monoclonal antibodies facilitated an enormous progress in modern medicine in the last years. The targeted inhibition of defined molecular structures allows therapeutic concepts, which before were inconceivable. There are numerous antibodies in clinical use within the area of tumour therapy, chronically inflammatory diseases, transplantation, infections and also in cardiovascular medicine. Different antibody formats are used such as IgG molecules, Fab fragments and single chain antibodies. Single chain antibodies represent the smallest functional form of the antibody and are used preferentially as recombinant antibodies. The therapeutic possibilities of antibody technology are extended by fusion to radioactive or therapeutically active substances. This review focuses on the application of antibodies and fusion proteins as antithrombotic and fibrinolytic drugs. The use of antibodies allows the development of inhibitory agents with clearly defined functional properties, as for example for activation-specific GPIIb/IIIa-blockade. In addition antibodies can be used for targeting antithrombotic and fibrinolytic agents to the thrombus, allowing an effective local action with less bleeding complications.

Carrying out the Medicine/Public Health Initiative: the roles of preventive medicine and community-responsive care.

Leaders in medicine and public health, recognizing the inherent interdependency of these fields, established the Medicine/Public Health Initiative in the mid-1990s as "an evolving forum in which representatives of both sectors can explore their mutual interests in improving health and [can] define collaborative mechanisms to achieve that goal." The Initiative's participants developed six goals that they and others in medicine and public health across the nation should implement: engage the community; change the education process; create joint research efforts by clinical, public health, and preventive medicine investigators; develop a shared view of illness between medicine and public health; work together to provide health care; and work jointly to develop health care assessment measures. The authors describe the six goals in depth and explain the important combined roles of clinically-oriented preventive medicine and community-oriented preventive medicine--as practiced in a model of health care delivery called community-oriented primary care (COPC)--in implementing the Initiative's goals. They then report recent efforts, including two in Boston and Dallas, to merge medicine and public health, and state that academic health centers, which are in the process of reshaping themselves, can help themselves as well as the public by embracing their key role in the effort to integrate medicine and public health. In particular, they can expand and strengthen existing training programs in preventive medicine and COPC or add these programs to their curricula.

Waldenström's macroglobulinemia: report of a case with pulmonary involvement and recurrent pneumococcal sepsis after pneumococcal vaccination.

A patient with Waldenström's macroglobulinemia who presented with pleuropulmonary manifestations is described. The course was complicated by recurrent Streptococcus pneumoniae infections despite pneumococcal immunization.

Antibiotic prophylaxis in severe acute pancreatitis.

Severe acute pancreatitis is considered to be a subgroup of acute pancreatitis with the development of local and/or systemic complications. A significant correlation exists between the development of pancreatic necrosis, the frequency of bacterial contamination of necrosis and the evolution of systemic complications. Bacterial infection and the extent of necrosis are determinants for the outcome of severe acute pancreatitis. The late course of necrotizing pancreatitis is determined by bacterial infection of pancreatic and peripancreatic necroses. Mortality increases from 5-25% in patients with sterile necrosis to 15-28% when infection has occurred. The use of prophylactic antibiotics has been recommended in patients with necrotizing pancreatitis. Several controlled clinical trials demonstrated a significant reduction in pancreatic infections or a significant reduction of hospital mortality. However, the results of these clinical trials are controversial and not convincing. Recently, the largest randomized placebo-controlled, double-blind trial has been able to demonstrate that antibiotic prophylaxis with ciprofloxacin and metronidazole has no beneficial effects with regard to the reduction of pancreatic infection and the decrease of hospital mortality. The clinical data from this placebo-controlled trial do not support antibiotic prophylaxis in all patients with necrotizing pancreatitis, but in specific subgroups of patients with pancreatic necrosis and a complicated course.

[Guideline conformity and outcome of inpatient treatment for schizophrenia. A clinical comparison]. / Leitlinienkonformität und Behandlungsergebnisse in der stationären Schizophreniebehandlung. Ein Klinikvergleich.

Patient outcome and guideline conformity in inpatient schizophrenia treatment was systematically evaluated and compared with 597 patients across seven psychiatric hospitals. Patient structure and treatment processes showed a great variability between hospitals. Patient characteristics, especially mental state, and the chronicity of the disease were the strongest predictors of clinical outcome. Outcome evaluation using quality indicators is only possible after case-mix adjustment taking into account prognostic factors. A poorer average clinical outcome was associated with lower guideline conformity in a variety of treatment domains. After case-mix adjustment, benchmarking is an opportunity to improve quality of treatment and promote guideline conformity.

The New Programmes: Decentralized Medical Education in the USA: The WAMI Programme.

This article describes an experiment to provide decentralized medical education in Washington, Alaska, Montana and Idaho-four states sharing common problems of health care provision and education of health professionals, including physicians. Evaluation of eight years' experience with the programme shows that the goals are being met. The basic concept of the WAMI programme is applicable to other health disciplines and/or regions with similar geographic, financial, educational and health care challenges.

The WAMI Program: 25 years later.

The Washington, Alaska, Montana and Idaho (WAMI) Program is a four-state decentralized medical education program initiated at the University of Washington School of Medicine (UWSM) in 1972 with the goals of: (1) admitting more students to medical school from all states, (2) training more primary care physicians, (3) bringing the UWSM's resources to needy communities, (4) redressing the maldistribution of physicians by placing more MDs in predominantly rural states and (5) avoiding new construction costs. The program consists of a University Phase and a Community Phase, the latter extending to residency/postgraduate medical training. Thirty-three years on, and now renamed WWAMI (with the inclusion of the State of Wyoming), nearly 1200 students have been admitted to the program, with 5947 clerkship experiences and 2282 resident rotations, and the original goals of this experiment in decentralized medical education have been largely met. Almost half of all residents supported by the program return home to practice, and of graduates who underwent a part of their training in Alaska, Montana and Idaho, 64.7% returned home to practice. This paper reports on some lessons learned and speculates whether the WAMI program can keep pace with the rapid changes in medical education.

Surgical treatment of posterior fossa tumors in infancy and childhood: techniques and results.

In a collective of 72 children with tumors of the posterior fossa, the preoperative diagnosis, operation planning and performance, and use of additional procedures, like the preliminary ventricular drainage and interventriculostomy are described. The extent of intra- and postoperative complications is given. Postoperative lethality was 0% in the group operated on between 1979 and 1991. The responsible factors are discussed. The findings support the opinion of ALBRIGHT (1989) that the prognosis for such patients is most promising in the hands of a specialist in pediatric neurosurgery.

Orthopedic and neurosurgical treatment of severe kyphosis in myelomeningocele.

Kyphosis in myelomeningocele is characterized by a complex pattern of problems during development and therapy. On the one hand, decompensation of upright posture leads to loss of sitting ability and social integration; on the other hand, accompanying malformations and trophic alterations threaten the physical integrity and performance. Neurologic function, cerebrospinal fluid (CSF) circulation, skeletal deformity and the urinary transport system need to be kept in mind and need to be treated with cooperation between the different specialties. Especially during serious surgical interventions such as spinal surgery, neither the nervous system nor the kidneys must be ignored. Sixteen patients underwent kyphectomy in the Orthopedic Department of the University of Mainz between 1993 and 1997, all of them supervised by the Neurosurgical Department. In 13 cases, transversal myelotomy was performed. No insufficiency of CSF circulation was seen; neither were there any CSF fistulae. Particular problems arose from the skin and soft tissue above the gibbus, the lack of muscles and the regeneration deficiency caused by trophic disorders. Therefore, a significantly higher complication rate was found than with other correctional operations.

[Amiodarone-induced bilateral optic atrophy--a case report]. / Amiodaron-induzierte bilaterale Optikusneuropathie. Eine Kasuistik.

We report a case of visual loss and bilateral papilloedema under therapy with the antiarrhythmic substance amiodarone, which is used in treatment of refractory and life-threatening supraventricular and ventricular cardial tachyarrhythmias. After excluding intracranial hypertension, local tumors and an inflammatory genesis we consider this case to be an amiodarone-induced toxic opticusneuropathy. Amiodarone, a diiodated benzofuran derivative, is a cationic amphiphilic drug, which is able to cause ceratopathy and neuropathy. The rarely described and less known opticusneuropathy caused problems in differential diagnosis. A brief review about current knowledge of pathophysiology, differential diagnosis and course of illness is presented.

[Perioperative infection prophylaxis in gastrointestinal surgery]. / Perioperative Infektionsprophylaxe in der Viszeralchirurgie.

Antibiotic perioperative prophylaxis is known to reduce postoperative infections and is generally administered as single-dose regimen today. Effective prophylaxis requires plasma- and tissue concentrations above the MIC of the expected bacterial spectrum throughout the whole operation from skin incision to wound closure. In longlasting operations a second dose after 4 hours is recommended. Indications for antibiotic prophylaxis are clean-contaminated or contaminated procedures according to Cruse and in patients with elevated risk of infection. Generally antibiotic prophylaxis is administered intravenously. Chinolons achieving high tissue- and plasmalevels and showing a broad antibacterial spectrum seem appropriate to be used for oral prophylaxis. In a prospective study in 36 patients pharmocokinetics of ofloxacin were measured perioperatively and proper plasma- and tissue concentrations were attained. A following prospective randomized study in 56 patients undergoing colonic or pancreatic resections oral prophylaxis did not show a higher infection rate compared with a standard intravenous prophylaxis. Therefore oral prophylaxis seems to be an attractive option, its effectivity needs to be proven by studies with sufficiently high patient numbers.

Botulinum toxin treatment of synkinesia and hyperlacrimation after facial palsy.

OBJECTIVES: To investigate the effects of injection of botulinum toxin type A (BTX A) into the orbicularis oculi muscle and lacrimal gland in patients with aberrant regeneration after facial palsy (facial synkinesias and hyperlacrimation). METHODS: The effect of the toxin injection (on average 75 mouse units of BTX A) into the orbicularis oculi muscle on facial synkinesias was assessed on a five point (0 to 4) scale in 10 patients with aberrant regeneration of facial nerve fibres after a peripheral facial nerve palsy. Six patients underwent a videographic control, which was assessed by a blinded independent investigator. In two patients with hyperlacrimation an extra dose of botulinum toxin (on average 20 mouse units BTX A) was injected into the lacrimal gland and the effect was assessed using the Schirmer test and on a three point scale. RESULTS: Botulinum toxin type A had a good to excellent (grades 3 and 4) effect over an average of six months after 91% of injections. In 9% the injections had a moderate (grade 2) effect. Patients with hyperlacrimation showed a nearly complete recovery. There were no systemic side effects but focal side effects due to a temporary weakness of the orbicularis oculi muscle were not uncommon. CONCLUSIONS: Botulinum toxin type A is the treatment of choice in motor and autonomic effects of aberrant regeneration of facial nerve after a peripheral palsy. The required dose is similar to or slightly lower than the dose usually recommended for hemifacial spasm.

Efficacy of oral ofloxacin for single-dose perioperative prophylaxis in general surgery--a controlled randomized clinical study.

BACKGROUND: Perioperative antibiotic prophylaxis surely reduces surgical infection rate. Pharmacokinetic data of oral ofloxacin in combination with its antibacterial spectrum suggest effective protection against perioperative infection. In addition, costs, adverse effects, and induction of microbial resistance are low. Therefore we performed a controlled randomized study comparing oral and intravenous single dose prophylaxis. METHODS: A total of 61 patients undergoing colonic or pancreatic resection randomly received either a single dose standard intravenous prophylaxis or ofloxacin 400 mg and metronidazole 500 mg orally 2 h before surgery. Postoperative infections were recorded for 3 weeks. RESULTS: Groups were very well comparable regarding age, overweight, concomitant disease, type and duration of surgery, blood loss, and volume support. Infectious complications occurred in 14.8% after parenteral and 3.3% after enteral antibiotic prophylaxis. There was no difference in post-operative hospital stay. CONCLUSION: The data demonstrate that single-dose oral ofloxacin is at least as effective as a standard intravenous prophylaxis in patients with colonic or pancreatic resection. It offers significant advantages regarding costs and ease of administration.