Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial.
Patients were randomly assigned, in a double-blinded fashion, ...to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations.
Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin.
These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.
Fabry disease is an X-linked lysosomal deficiency of alpha-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It ...is associated with early-onset stroke and kidney and heart failure.
Using (15)O H(2)O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of alpha-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels.
These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy.
Thigh Muscle Injuries in Youth Soccer Cloke, David; Moore, Oliver; Shab, Talib ...
The American journal of sports medicine,
02/2012, Letnik:
40, Številka:
2
Journal Article
Recenzirano
Background: Participation in soccer at younger ages with attendant risk of muscle injury is increasing.
Purpose: To delineate patterns of thigh muscle injury and predictors of recovery in male youth ...soccer academy players.
Study Design: Cohort study (prognosis); Level of evidence, 2.
Methods: Forty-one English Premiership soccer academy squads (all male, aged 8-16 years) over a 5-year period comprising 12 306 player seasons were studied prospectively for pattern, mechanism, and outcome after thigh muscle injury. Event analysis was used to identify independent predictors of slow recovery.
Results: A total of 1288 injuries were recorded representing an incidence (mean SD) of 0.42 (0.24) per thousand hours of training with a mean annual incidence of 0.52. Midfield players received the most injuries, followed by defense and attack positions. The quadriceps muscle group was most likely to be injured. There were 345 reinjuries (27%). Median time off for a primary injury was 13 days (interquartile range, 7-22 days) and 12 days (7-21 days) following a reinjury. Risk of such injury increased as the game progressed toward the end of the first half period (P = .028), and this risk persisted throughout the entire second half. There were 2 peaks of incidence (January and September). The percentage of the total for hamstring, adductor, and quadriceps injuries did not significantly change with player age. However, the proportion of injuries that were severe increased with age of player (t = 3.72, P = .010). Poor prognostic factors for recovery were hamstring injuries (z = 2.182, P = .029), contact injury (z = −3.137, P = .002), and older age (z = −2.2298, P = .022).
Conclusion: The risk for prolonged recovery from thigh muscle injury was found to increase with age of the player and contact mechanism. The risk of injury increased toward the end of the first half, and this risk persisted throughout the second half. Delayed recovery was significantly associated with a hamstring muscle injury, first injury, and contact mechanism. This study, for the first time, allows identification of youth male soccer players at high-risk for prolonged symptoms after thigh muscle injury.
We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This ...study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples.
Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables.
Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2-negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with > or = 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2-positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (> or = 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2-positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup.
PN2A immunostaining identified a subset (approximately 12% of ErbB-2-positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (> or = 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.
The specialty of Child and Adolescent Psychiatry was formally recognised in the 1930s. The Faculty of Child and Adolescent Psychiatry was established in 1964 in Australia, as a subspecialty in The ...Royal Australian and New Zealand College of Psychiatrists (RANZCP). The aim of the current article is first to provide a brief summary and overview of the current status of Child and Adolescent Psychiatry (CAP), followed by an outline of the requirements of the Training Program for CAP in Australia and New Zealand. The training required to become a fully qualified child and adolescent psychiatrist in Australia and New Zealand consists of different stages and takes the form of competency-based training. Information relating to assessment types, supervision and research requirements is also described. Accreditation procedures for the training program are stipulated by RANZCP to monitor standards and to ensure consistency within the programs delivered across Australia and New Zealand. Employment opportunities for trainees upon completion of the program are discussed. In summary, this article highlights the requirements of the training programs for CAP in Australia and New Zealand.
Reperfusion injury of ischemic tissue represents an acute inflammatory response that can cause significant morbidity and mortality. The mechanism of injury is not fully elucidated, but recent studies ...indicate an important role for natural antibody and the classical pathway of complement. To test the hypothesis that injury is initiated by specific IgM, we have screened a panel of IgM-producing hybridomas prepared from peritoneal cells enriched in B-1 cells. One clone, CM22, was identified that could restore pathogenic injury in RAG-1-/-mice in an intestinal model of ischemia/reperfusion (I/R). In situ activation of the classical pathway of complement was evident by deposition of IgM, complement C4, and C3 in damaged tissue after passive transfer of CM22 IgM. Sequence analysis of CM22 Ig heavy and light chains showed germ-line configurations with high homology to a VHsequence from the B-1 repertoire and a VKof a known polyreactive natural IgM. These data provide definitive evidence that I/R injury can be initiated by clonally specific natural IgM that activates the classical pathway of complement. This finding opens an avenue for identification of I/R-specific self-antigen(s) and early prevention of injury.
Antibiotics are still prescribed to most patients attending primary care with acute sore throat, despite evidence that there is modest benefit overall from antibiotics. Targeting antibiotics using ...either clinical scoring methods or rapid antigen detection tests (RADTs) could help. However, there is debate about which groups of streptococci are important (particularly Lancefield groups C and G), and uncertainty about the variables that most clearly predict the presence of streptococci.
This study aimed to compare clinical scores or RADTs with delayed antibiotic prescribing.
The study comprised a RADT in vitro study; two diagnostic cohorts to develop streptococcal scores (score 1; score 2); and, finally, an open pragmatic randomised controlled trial with nested qualitative and cost-effectiveness studies.
The setting was UK primary care general practices.
Participants were patients aged ≥ 3 years with acute sore throat.
An internet program randomised patients to targeted antibiotic use according to (1) delayed antibiotics (control group), (2) clinical score or (3) RADT used according to clinical score.
The main outcome measures were self-reported antibiotic use and symptom duration and severity on seven-point Likert scales (primary outcome: mean sore throat/difficulty swallowing score in the first 2-4 days).
The IMI TestPack Plus Strep A (Inverness Medical, Bedford, UK) was sensitive, specific and easy to use. Lancefield group A/C/G streptococci were found in 40% of cohort 2 and 34% of cohort 1. A five-point score predicting the presence of A/C/G streptococci FeverPAIN: Fever; Purulence; Attend rapidly (≤ 3 days); severe Inflammation; and No cough or coryza had moderate predictive value (bootstrapped estimates of area under receiver operating characteristic curve: 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection. In total, 38% of cohort 1 and 36% of cohort 2 scored ≤ 1 for FeverPAIN, associated with streptococcal percentages of 13% and 18%, respectively. In an adaptive trial design, the preliminary score (score 1; n = 1129) was replaced by FeverPAIN (n = 631). For score 1, there were no significant differences between groups. For FeverPAIN, symptom severity was documented in 80% of patients, and was lower in the clinical score group than in the delayed prescribing group (-0.33; 95% confidence interval -0.64 to -0.02; p = 0.039; equivalent to one in three rating sore throat a slight rather than moderately bad problem), and a similar reduction was observed for the RADT group (-0.30; -0.61 to 0.00; p = 0.053). Moderately bad or worse symptoms resolved significantly faster (30%) in the clinical score group (hazard ratio 1.30; 1.03 to 1.63) but not the RADT group (1.11; 0.88 to 1.40). In the delayed group, 75/164 (46%) used antibiotics, and 29% fewer used antibiotics in the clinical score group (risk ratio 0.71; 0.50 to 0.95; p = 0.018) and 27% fewer in the RADT group (0.73; 0.52 to 0.98; p = 0.033). No significant differences in complications or reconsultations were found. The clinical score group dominated both other groups for both the cost/quality-adjusted life-years and cost/change in symptom severity analyses, being both less costly and more effective, and cost-effectiveness acceptability curves indicated the clinical score to be the most likely to be cost-effective from an NHS perspective. Patients were positive about RADTs. Health professionals' concerns about test validity, the time the test took and medicalising self-limiting illness lessened after using the tests. For both RADTs and clinical scores, there were tensions with established clinical experience.
Targeting antibiotics using a clinical score (FeverPAIN) efficiently improves symptoms and reduces antibiotic use. RADTs used in combination with FeverPAIN provide no clear advantages over FeverPAIN alone, and RADTs are unlikely to be incorporated into practice until health professionals' concerns are met and they have experience of using them. Clinical scores also face barriers related to clinicians' perceptions of their utility in the face of experience. This study has demonstrated the limitation of using one data set to develop a clinical score. FeverPAIN, derived from two data sets, appears to be valid and its use improves outcomes, but diagnostic studies to confirm the validity of FeverPAIN in other data sets and settings are needed. Experienced clinicians need to identify barriers to the use of clinical scoring methods. Implementation studies that address perceived barriers in the use of FeverPAIN are needed.
Current Controlled Trials ISRCTN32027234.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 6. See the NIHR Journals Library website for further project information.
The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project ...trial R-04 compared four chemotherapy regimens administered concomitantly with RT.
Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery).
From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001).
Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred.
To analyze the impact of a conservative strategy of management in patients with necrotizing pancreatitis, reserving intervention for patients with documented infection or the late complications of ...organized necrosis.
The role of surgery in patients with sterile pancreatic necrosis remains controversial. Although a conservative approach is being increasingly used, few studies have evaluated this strategy when applied to the entire spectrum of patients with necrotizing pancreatitis.
The authors reviewed 1,110 consecutive patients with acute pancreatitis managed at Brigham and Women's Hospital between January 1, 1995, and January 1, 2000, focusing on those with pancreatic necrosis documented by contrast-enhanced computed tomography. Fine-needle aspiration, the presence of extraintestinal gas on computed tomography, or both were used to identify infection.
There were 99 (9%) patients with necrotizing pancreatitis treated, with an overall death rate of 14%. In three patients with underlying medical problems, the decision was made initially not to intervene. Of the other 62 patients without documented infection, all but 3 were managed conservatively; this group's death rate was 11%. Of these seven deaths, all were related to multiorgan failure. Five patients in this group eventually required surgery for organized necrosis, with no deaths. Of the 34 patients with infected necrosis, 31 underwent surgery and 3 underwent percutaneous drainage. Only four (12%) of these patients died, all of multiorgan failure. Of the total 11 patients who died, few if any would have been candidates for earlier surgical intervention.
These results suggest that conservative strategies can be applied successfully to manage most patients with necrotizing pancreatitis, although some will eventually require surgery for symptomatic organized necrosis. Few if any patients seem likely to benefit from a more aggressive strategy.
Change history: In this Letter, the y-axis values in Fig. 3f should go from 4 to -8 (rather than from 4 to -4), the y-axis values in Fig. 3h should appear next to the major tick marks (rather than ...the minor ticks), and in Fig. 1b, the arrows at the top and bottom of the electron-scale current sheet were going in the wrong direction; these errors have been corrected online.
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