Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis causing endothelial dysfunction, an early sign of atherogenesis. Symmetric dimethylarginine (SDMA) does not inhibit NO synthases. Peripheral arterial disease (PAD) is a systemic indication of atherosclerosis. METHODS: We assessed the associations between both ADMA and SDMA blood levels and major cardiovascular and cerebrovascular events or death from any cause within a 5-year follow-up in the multicentre getABI trial. From a cohort of 6821 primary care patients, aged ≥65 years, all 1260 patients with prevalent PAD were compared with a random sample of 1187 non-PAD controls. A total of 11,544 patient-years were documented. Multivariate risks were calculated by Cox proportional hazard models, adjusting for PAD, renal dysfunction and other important cardiovascular risk factors. RESULTS: We documented 390 deaths, 296 cardiovascular events and 98 cerebrovascular events. Increased ADMA levels in the 4th quartile were significantly associated with total mortality [hazard ratio (HR) 1.41; 95% CI 1.14-1.74] and with cardiovascular events (HR 1.32; 95% CI 1.03-1.69), but there was a nonsignificant association with cerebrovascular events (HR 1.50; 95% CI 0.98-2.29). Increased SDMA was only just significantly associated with mortality (HR 1.27; 95% CI 1.01-1.59). In PAD patients compared with non-PAD controls, only mean SDMA concentration was considerably increased (0.52 µmol L(-1) vs. 0.48 µmol L(-1); P < 0.001) mainly because of a highly significant association with impaired renal function. CONCLUSION: These data suggest that ADMA but not SDMA is an independent risk marker for death from any cause or from cardiovascular events. The association between SDMA and mortality is in part explained by a close link between SDMA and renal function.

Differences in Chinese diagnoses for migraine and tension-type headache: an analysis of the German acupuncture trials (GERAC) for headache.

A growing number of clinical trials are testing Chinese acupuncture in the management of headache disorders. Little is known, however, about the relationship between International Headache Society diagnostic criteria and traditional Chinese medicine (TCM) diagnosis in primary headache disorders. We conducted a secondary analysis of the data of the prospective, controlled, blinded German acupuncture trials for migraine and tension-type headache. Data were collected from 1042 headache patients, of whom 633 were diagnosed with migraine and 409 with tension-type headache. We found that the diagnoses of migraine and tension-type headache were mirrored by different patterns of TCM diagnoses, with the patterns Liver Yang Rising, Liver Fire Rising, and Phlegm appearing to be best suited to differentiating between migraine and tension-type headache. Although not unexpected, given that the diagnosis of primary headache disorders in both diagnostic systems is based largely on the nature and quality of patient-reported symptoms, this finding suggests that migraine and tension-type headache are associated with different patterns of TCM diagnosis.

[Quality of care after distal radius fracture in Germany. Results of a fracture register of 1,201 elderly patients]. / Die stationäre Behandlungsqualität der distalen Radiusfraktur in Deutschland: Ergebnisse eines Frakturregisters mit 1201 älteren Patienten.

BACKGROUND: This study is the first to document the quality of inpatient care provided to elderly patients with distal radius fracture in Germany. PATIENTS AND METHODS: Inpatient care provided to 1,201 patients age 65 or older with isolated distal radius fracture was documented in a prospective cohort study conducted at 242 acute care clinics in Germany between January 2002 and September 2003. RESULTS: The median patient age was 75, and nearly 90% of patients were female. Approximately 71% of patients were classified as ASA I or II, and 28% were ASA III. The most common comorbidity was arterial hypertension (60%). Seventy-five percent of patients were admitted on the day of the accident; of these, 63% had surgery on the same day, and 20% on the following day. The primary form of anaesthesia was general anaesthesia (55%). The predominant fracture management procedure was percutaneous K-wire osteosynthesis (56% of cases), followed by plate osteosynthesis (44%). The length of hospital stay after plate osteosynthesis (median 8.5 days) was more than twice as long as after K-wire osteosynthesis (median 4 days). The rate of postoperative complications typical of each procedure was around 10%. Roughly 90% of patients were discharged to home. Although evidence of osteoporosis was observed in 62% of women and 50% of men, only 7.9% of patients were prescribed osteoporosis-specific medication. CONCLUSIONS: Unexpected findings were the predominance of general anaesthesia and percutaneous K-wire osteosynthesis. Osteoporosis, affecting a majority of elderly women, is neglected in clinical practice. Good quality of care is reflected by the low rate of complications.

Long-term improvement in pain coping for cLBP and gonarthrosis patients following body needle acupuncture: a prospective cohort study.

BACKGROUND: Little is known about potential long-term effects of body acupuncture. The aim of the study was to determine such long-term effects 3 and 6 months after the end of a course of acupuncture treatment for chronic low-back pain (cLBP) or chronic pain caused by gonarthrosis. METHODS: Prospective cohort study with patients who had received 10 sessions of needle body acupuncture within a maximum of 10 weeks. Data source was our survey of all patients receiving acupuncture treatment in Germany. A total of 1096 eligible patients with cLBP or gonarthrosis pain were identified (68.1% female) and invited by letter to participate in the study. Ultimately 249 patients remained, with no loss of representativeness. Two telephone interviews were conducted 3 and 6 months after the last acupuncture session using standardized questionnaires, available as electronic case report forms. The primary target criteria were self-assessment of pain tolerability prior to the start of acupuncture and after the end of treatment, and pain intensity (GCPS) over time. Secondary target criteria were changes to functional impairment (HFAQ for cLBP, WOMAC for gonarthrosis), quality of life (SF12), depression (CES-D) and patient global assessment of treatment effectiveness (PGA). For the indication cLBP, pain-related fear avoidance beliefs (FABQ) were also queried. RESULTS: Pain tolerability before acupuncture was reported as being significantly worse than pain tolerability at the time of the two post-acupuncture interviews. The scores for all post-acupuncture questionnaires showed no significant changes over time, with the exception of treatment effectiveness for gonarthrosis. Mean scores for each of the questionnaires at the 3 and 6 month follow-up interviews were as follows: cLBP: Pain tolerability (pre: 6.8, post: 3.4 / 3.4), pain intensity (41.8 / 42.6), PGA (2.4 / 2.6), SF12 physical (35.8 / 35.8), SF12 mental (45.3 / 46.9), CES-D (14.9 / 14.9), HFAQ (67.2 / 67.1), FABQ total (2.9 / 2.9). GONARTHROSIS: Pain tolerability (pre: 6.9, post: 3.6 / 3.9), pain intensity (42.9 / 42.8), PGA (2.6 / 2.9), SF12 physical (32.2 / 31.3), SF12 mental (45.0 / 46.2), CES-D (15.6 / 14.7), WOMAC total (34.6 / 34.0). CONCLUSIONS: Pain tolerability was significantly improved after acupuncture and remained so up to 6 months after treatment. The mean scores of almost all questionnaires did not change significantly between 3 and 6 months. We therefore conclude that acupuncture had a long-term effect on important aspects of cognitive and emotional pain coping.

An internal standard for verifying the accuracy of serious adverse event reporting: the example of an acupuncture study of 190,924 patients.

BACKGROUND: Reporting of all serious adverse events (SAEs) is a requirement for regulatory approval of a drug. Can equally rigorous reporting standards be expected in studies of non-drug treatments and how can underreporting, if any, be detected and proven? Using data from our large-scale prospective cohort study of acupuncture on outpatients, we examine the use of an internal standard, a principle taken from laboratory medicine, to quantify real event rates. METHODS: A total of 190,924 patients (68.6% women) seeking treatment for chronic pain (headache, low back pain, coxarthrosis or gonarthrosis) from 12,000 physicians in private practice in Germany were observed during a six-month period ending in May 2002. Most received ten sessions of body acupuncture. Mean treatment time was six weeks. All practitioners were certified in acupuncture and received written instructions on completing forms for basic patient data and SAE monitoring. They were also informed that payment by insurers would be made only upon return of the completed form. All SAEs occurring between start of the first acupuncture session and end of the last one were to be reported, whether causally related to the treatment or not. Multiple minor adverse events (AEs) per single patient were to be reported only once. As the internal standard we chose the expected number of deaths, based on the death rate for the German population, adjusted for age, sex distribution and mean observation time of our study patients. RESULTS: 45 SAEs and 14,404 AEs were reported (i.e. 2.4 SAEs and 754 AEs per 10,000 patients). The number of reported deaths (9) was only 5% of the statistically expected number (180). Applying the resulting correction factor of 20 to all reported SAEs, resulted in 900 expected SAEs (versus 45 reported) or 47 per 10,000 patients. CONCLUSIONS: Without verifying the accuracy of a measurement, results remain speculative. Our internal standard for the first time provides a means of verifying the accuracy of the reported SAE rate and correcting it to the statistically expected SAE rate.

Lack of pharmacokinetic interaction between dextromethorphan, coumarin and mephenytoin in man after simultaneous administration.

The possible interference of simultaneously given dextromethorphan (10 mg dextromethorphan-HBr-H2O), coumarin (10 mg), and mephenytoin (100 mg (R/S)-mephenytoin) on oxidative routes of drug metabolism performed by different cytochrome P450 enzymes and the possibility to detect all of the three substances and their metabolites in urine were investigated in 12 healthy subjects. The concentrations of parent drugs and main metabolites were measured in urine using modified HPLC-methods. All subjects were extensive metabolizers of mephenytoin and dextromethorphan as calculated using hydroxylation index (HI) for mephenytoin and as seen in the quantification of urinary dextromethorphan/dextrophan. A combined determination of coumarin and dextromethorphan with their metabolites or of coumarin and mephenytoin with their metabolites in urine is possible. The combined HPLC separation of all parent compounds and metabolites, however, is not useful because of the necessity to treat the urine samples in very different ways. An overlapping of retention times of the substances in HPLC does not occur. With it a simultaneous administration of all three drugs is possible. A following collection of urine over a period of 8-12 h serves for characterizing activities of different cytochrome P450 enzymes of patients. So particularly the influence of a long term drug therapy on the hydroxylation activities of these cytochromes is easily definable without the disturbing influence of intraindividual variation of drug oxidation with time.

Acupuncture points are large fields: the fuzziness of acupuncture point localization by doctors in practice.

BACKGROUND: Acupuncture textbooks, schools, practitioners and clinical researchers designing randomized controlled trials on acupuncture all assume that acupuncture points are small and must be located precisely. METHOD: Seventy-one medical doctors with ≥200 h acupuncture training and ≥2 years of clinical experience independently identified 23 commonly used acupuncture points on a male volunteer, using sticky transparent films with an X/Y grid placed asymmetrically around acupuncture points. RESULTS: For each acupuncture point, the field covering 95% (68%) of all point locations varied from 2.7 (0.7) cm(2) for PC-6 up to 41.4 (10.2) cm(2) for ST-38. Commonly-used acupuncture points showed unexpectedly large variance in location: 95% (or 68%) areas were SP-6: 12.2 cm(2) (3.0 cm(2) ), ST-36: 20.7 cm(2) (5.1 cm(2) ), LI-15: 18.7 cm(2) (4.6 cm(2) ), BL-23: 22.4 cm(2) (5.6 cm(2) ) and BL-54: 22.5 cm(2) (5.6 cm(2) ). Points close to anatomical landmarks (forearm, ankle, poplitea; BL-60, BL-40, TW-5, PC-6) were located with less variance. Precision of point location was independent of length of acupuncture experience, kind of training or medical specialty. CONCLUSIONS: In respect to the high degree of variation in the localization of acupuncture points, we suggest that the term 'acupuncture field' is more appropriate than 'acupuncture points' to describe the clinical reality; for the design of sham-controlled acupuncture trials, we recommend a minimum distance of 6 cm between verum and sham points on face, hands and feet, and up to 12 cm for all other parts of the body.

[Do physicians overestimate effects of acupuncture treatment?]. / Uberschätzen Arzte die Effekte der Akupunkturbehandlung?

BACKGROUND: Physicians' ratings about their patients' pain prove to be invalid compared to patients' ratings. This is especially true if pain rating acts as an indicator for therapy outcome. The aim of this study was to compare physicians' and patients' ratings of pain relief following acupuncture and to identify correlations between patient characteristics and potential miscalibrations. PATIENTS AND METHODS: In a cross-sectional study 291 pain patients with gonarthrosis or chronic low back pain and their attending physicians were asked to give their rating of patients' pain relief following acupuncture. Patients were interviewed by telephone, and doctors responded to questionnaires. RESULTS: The proportion of false-positive physicians' ratings was 81% referring to patients without self-reported benefit from acupuncture. Just every fifth patient without pain relief was correctly classified by his physician. There was no correlation between patients' characteristics and false-positive ratings of physicians. CONCLUSIONS: Evaluation of treatment in daily medical routine should be primarily based on information provided by patients.

[German Acupuncture Trials (gerac) address problems of methodology associated with acupuncture studies]. / Zur Problematik von Akupunkturstudien am Beispiel der Methodik von gerac.

OBJECTIVE: Conflicting or ambivalent findings on the effectiveness of body acupuncture in pain treatment are often attributed to flaws in study methodology. The paper describes the methodology used for the German Acupuncture Trials (gerac), which demonstrates that it is possible to design acupuncture studies in accordance with the standards of good clinical practice. METHOD: Approximately 1000 chronic pain sufferers per indication (migraine, tension-type headache, low back pain (cLBP), or gonarthrosis) are randomly allocated to one of three treatment groups (verum acupuncture, sham acupuncture, or established conservative therapy). Patients are blind to the type of acupuncture. All patients receive ten sessions of treatment (two per week) with an option of adding five more treatments in cases of slight but insufficient improvement (number of headache days or von Korff pain score). Participating physicians are in private practice, representing a variety of specialties. All have completed at least a 140-hour training course in acupuncture. Mandatory and optional verum and sham points are predefined. The point selection is individualized according to the criteria of traditional Chinese medicine (TCM). Primary outcome measures are number of headache days per month, von Korff Graded Chronic Pain Scale or Hannover Functional Ability Questionnaire (cLBP), or WOMAC scores (gonarthrosis). Data are assessed by trained telephone interviewers not involved in treatment and blind to types of acupuncture. PRESENT STATUS: Over 500 participating physicians in ten urban areas of Germany. Patient recruitment for cLBP and gonarthrosis was completed in November 2003 and March 2004 respectively. Recruitment for chronic headaches will be completed in autumn 2004. CONCLUSIONS: The gerac trials prove that it is possible to design and carry out acupuncture studies in accordance to stringent standards of methodology and clinical practice. The results will form a basis for the assessment of acupuncture effectiveness in Germany and abroad.

[The alcohol method for determining total body water: comparison with heavy water (D2O)]. / Die Alkoholmethode zur Bestimmung des Gesamtkörperwassers: Vergleich mit Schwerem Wasser (D2O).

The determination of Total Body Water (TBW) by means of even dilution of the perorally administered indicator substance ethanol in the TBW-space is successful with a precision which is in direct comparison with other dilution-indicators, even superior that of D2O, which can be considered as a standard indicator substance for TBW. Thus, also indirectly, another proof emerges for the fact that ethanol dissolves exclusively in the body water. Applying the alcohol-method shows that even small changes of a few hundred milliliters of the body water volume, as they appear during the menstruation cycle, are detectable. Even in patients with a terminal renal failure and the risk of pathological water retention of several liters, there is no criterion which might exclude the TBW-determination by means of the dilution of slight quantities of ethanol. Finally, considering the possibility to determine the blood alcohol concentration (after a complete distribution in the TBW-space) with sufficient precision using a breath ethanol analyzer of the latest generation, the possibility emerges to carry out TBW-determination in patients and volunteers essentially noninvasive.

Comparison of D2O and ethanol dilutions in total body water measurements in humans.

Total body water was measured by ethanol dilution and D2O stable isotope dilution in a group of 20 healthy volunteers (5 females and 15 males), predominantly 23- to 31-year-old students. Both indicator substances were given orally with an ethanol burden of 0.8 g/kg body weight and a D2O burden of 0.1 g/kg body weight after 12-h food and fluid restriction. This first direct comparison of total body water (TBW) from ethanol and D2O dilutions revealed the ethanol compartments to be smaller than those of D2O. The quotient of TBW (ethanol)/TBW (D2O) was 97.7%, which is the order of the quotient TBW (H2(18)O)/TBW (D2O) ( = 97%), well known from the literature and taken to represent relatively exactly the value of TBW overestimation (based on H/D exchange for acid protons) following D2O dilution [36]. Thus the value of TBW (ethanol) is almost identical to that of H2(18)O, which provides direct evidence that ethanol is distributed only in the body water.