Integration of genetic, clinical, and INR data to refine warfarin dosing.

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans.

Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.

The Effect of Metformin and Standard Therapy versus Standard Therapy alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial.

Nonalcoholic steatohepatitis (NASH) is increasing in prevalence and is related to underlying insulin resistance. The aim of this study was to assess the efficacy of metformin on the characteristic histopathologic lesions of NASH. This was a 12-month prospective, randomized, placebo-controlled trial comparing diet and exercise alone to diet, exercise and metformin in nondiabetic patients with insulin resistance and NASH. Patients were randomized to either group A or B. Group A received placebo, dietary counseling, recommendations for weight loss and exercise four times per week. Group B received long-acting metformin 500 mg daily (titrated to 1000 mg daily) plus dietary counseling, recommendations for weight loss and exercise four times per week. Histopathology was assessed at 12 months and biopsies were scored by two pathologists who were blinded to all data. Twenty-three subjects were screened and 19 were randomized to either group A (n »10) or group B (n» 9). Seven of the 10 subjects in group A completed the study including repeat liver biopsy while all patients in group B completed the study. Body mass index improved in both groups decreasing by 1.7 kg/m(2) in group A and 0.9 kg/m(2) in group B (not significant, control versus treatment). Homeostasis model assessment of insulin resistance scores improved in both groups decreasing by 1.14 in group A and 1.58 in group B (not significant, control versus treatment). No significant difference in histopathology was seen between groups on follow-up liver biopsy. Metformin appeared to have little effect in improvement in liver function tests or liver histology in nondiabetic patients with insulin resistance and NASH. Decrease in BMI through diet and exercise significantly improved HOMA-IR scores, serum aminotransferases and liver histology.

Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.

BACKGROUND: Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common. METHODS: In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. RESULTS: The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R(2) was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R(2) of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7-11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30-0.97). CONCLUSIONS: Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.

Silicone lymphadenopathy mimicking a lymphoma in a patient with a metatarsophalangeal joint prosthesis.

With lymph node enlargement, the possibility of a malignant process such as metastatic carcinoma or lymphoma needs to be excluded. This report describes a 47 year old woman with inguinal lymph node enlargement initially suspicious for lymphoma. Fine needle aspiration findings favoured reactive hyperplasia, but a malignant process could not be excluded. The final histological diagnosis was a foreign body granulomatous inflammatory response as a result of regionally disseminated silicone particles from an over looked metatarsophalangeal joint prosthesis. Because of the large number of joint prostheses world wide, it should be kept in mind that migration of wear particles can create granulomatous inflammation and node enlargement.

Androgen response to hypothalamic-pituitary-adrenal stimulation with naloxone in women with myotonic muscular dystrophy.

Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant inheritance characterized by multisystem disease, including myotonia, muscle-wasting and weakness of all muscular tissues, and endocrine abnormalities attributed to a genetic abnormality causing a defective cAMP-dependent kinase. We have previously reported that MMD patients demonstrate ACTH hypersecretion after endogenous CRH release stimulated by naloxone administration while manifesting a normal cortisol (F) response. Additionally, others have reported a reduced adrenal androgen (AA) response to exogenous ACTH administration in MMD patients. As ACTH stimulates the secretion of both AAs and F, it is possible that the discordant relationship of these hormones in MMD patients results from a defect of adrenocortical ACTH receptor function or postreceptor signaling or subsequent biochemical events. Furthermore, the molecular abnormality seen in MMD patients may suggest that the mechanism underlying the frequently observed discordances in the secretion of glucocorticoids and AAs (e.g. adrenarche, surgical trauma, severe burns, or intermittent glucocorticoid administration) are explainable solely via an alteration in the function of the ACTH receptor or postreceptor signaling. To ascertain whether the responses of F and AAs to endogenous ACTH diverged in this disorder, we prospectively studied the responses of these hormones to naloxone-stimulated CRH release in nine premenopausal women with MMD and seven healthy age and weight-matched control women. After naloxone infusion (125 micrograms/kg, i.v.), blood sampling was performed at baseline (i.e. -5 min) and at 30 and 60 min. In addition to the absolute hormone level at each time, we calculated the net increment (i.e. change) at 30 and 60 min and the area under the curve (AUC) for F, ACTH, dehydroepiandrosterone (DHA), and androstenedione (A4). Consistent with our previous study, MMD patients demonstrated higher ACTH levels at all sampling times except [minud]5 min. AUC analysis revealed the ACTHAUC values were significantly higher in MMD than in control women (457 +/- 346 vs. 157 +/- 123 pmol/min.L; P < 0.03), whereas the FAUC response did not differ between MMD and controls (13860 +/- 3473 vs. 13375 +/- 3465 nmol/min.L; P > 0.5). Despite the greater ACTH secretion, the baseline circulating dehydroepiandrosterone sulfate levels were significantly lower in MMD compared with control women (18 +/- 23 vs. 61 +/- 23 mumol/L; P < 0.002). The serum concentrations of A4 at baseline, 30 min, and 60 min and DHA levels at 30 and 60 min were also significantly lower in MMD vs. control women. Additionally, the A4AUC and DHAAUC values were significantly lower in MMD patients than in controls. Furthermore, the net response of DHA at 60 min to the endogenous ACTH increase was also reduced in MMD patients compared with that in control subjects (2.3 +/- 2.1 vs. 5.6 +/- 2.6 nmol/L; P < 0.02). In conclusion, in addition to ACTH hypersecretion to CRH-mediated stimuli, these data suggest that MMD patients have a defect in the adrenocortical response to ACTH, reflected in normal F and reduced DHA and A4 secretion. Whether this defect is inherent to the disease or simply reflects adaptive changes to chronic disease remains to be demonstrated. However, it is possible that further studies of the response of MMD patients to ACTH may reveal a mechanism that explains the frequently observed dichotomy in the secretion of glucocorticoids and AAs.

A heterotopic autoinnervated urinary neosphincter.

Twenty-six female adult New Zealand white rabbits underwent surgical denervation of a gracilis muscle to study the possibility of developing an autologous neosphincter innervated by the pudendal nerve. The study was conducted in 2 phases. In both Phase I and Phase II, the study group had the motor nerve to the gracilis, a branch of the obturator nerve and the pudendal nerve coapted in the perineum. The control group was left denervated. In Phase I, all muscle flaps were wrapped around the urogenital sinus. In Phase II, the muscle flaps were returned to their anatomic location. With bulbocavernosus reflex testing, 89% of the reinnervated group and 60% of the denervated group from Phase I and 86% of the reinnervated group and none of the denervated group from Phase II had a contractile response in the muscle flap. In Phase II, histologic examination of the gracilis muscle was suggestive of an early change in muscle myofiber physiology from fast twitch to slow twitch in the reinnervated group only. In the rabbit, a transplanted vascularized muscle flap, cross-innervated by the pudendal nerve has a reproducible response to bulbocavernosus reflex testing. This suggests that a transplanted muscle might be able to assume some of the characteristics of the voluntary urinary sphincter. The rabbit is a useful model in which to investigate the potential of the heterotopic neosphincter.

What makes targets redundant?

Two letter-classification experiments that investigated target-redundancy effects on reaction time (RT) were conducted. Both experiments were replicated with choice reaction time (CRT) and go/no-go (GNG) procedures. In each experiment, there were two single-target conditions, one with a noise letter and one without. In one experiment, the letter classes were two letters that could be of either case. In the second experiment, each class consisted of two different capital letters. In both experiments, there were two redundant-targets conditions, one with identical targets and one with the different members of a class. In both of the GNG experiments, redundancy gains were obtained comparing the different-targets condition with the no-noise, single-target condition. Redundant stimuli are ones that lead to the same response. Visually different stimuli may be processed in parallel and jointly activate a response. GNG procedures are more sensitive than CRT in the investigation of redundancy effects.

Primary popliteal venous aneurysm with recurrent pulmonary emboli.

Primary venous aneurysms are infrequently noted and rarely have clinical significance. An important exception, however, is an aneurysm of the popliteal vein that is known to be a source for pulmonary emboli. We present the case of a previously healthy 57-year-old man with recurrent episodes of occult pulmonary embolism. Initial diagnostic investigations were compatible with multiple pulmonary emboli, but no source was identified. Subsequently, an indium 111-labeled platelet scan confirmed a site of active thrombus formation in the right lower extremity above the knee. Magnetic resonance imaging defined a saccular aneurysm of the popliteal vein, which was confirmed by contrast venography. Thereafter, the patient had resection of the venous aneurysm and tangential venorrhaphy. After operation duplex scanning confirmed patency of the venous repair. This is the eleventh report in the English-language literature of pulmonary emboli suspected of having originated from a popliteal venous aneurysm.

Redundancy phenomena are affected by response requirements.

Results are reported for two go/no-go reaction time (RT) experiments, in which the redundant targets advantage was investigated. These experiments were replications of two earlier choice reaction time (CRT) experiments, in which letter stimuli were used. Important differences between the go/no-go RT experiments and the CRT experiments were obtained. Equal and significant redundancy advantages were obtained whether redundant targets were compared with a single target presented with a noise letter or without noise. In the CRT experiments, the advantage was not obtained in the comparison with a single target presented alone. Noise letters did not slow the RTs to single targets with which they were presented as was the case with CRT. Since the differing results of the two procedures depend on the response requirements, explanation of differing CRT data in terms of perceptual or attentional concepts is probably inappropriate. The presence and absence of response competition in the two situations may be the best interpretation. The results tend to support a conclusion of the parallel processing of two letter stimuli separated spatially by as much as 3 degrees.

Military nordic skiing injury profiles with two different types of NATO ski bindings.

Two different types of NATO ski bindings were compared during military-nordic ski training of a Marine Corps infantry battalion of 534 men, who sustained 26 injuries (3.75 injuries per 1,000 skier days). Twelve injuries occurred with the 224 subjects using the NATO 100 bindings. Fourteen injuries occurred with the 310 subjects using the NATO 120 bindings. A total of 133 days were lost from training in the NATO 100 cohort and 121 days from training in the NATO 120 cohort, a statistically significant difference. It is concluded that the NATO 120 binding is safer.