Search

The use of antibiotics directly correlates with the increase in antimicrobial resistance (AMR). Targeting novel antibiotics to patients with multidrug-resistant (MDR) pathogens should enhance their durability and slow development of resistance. The discovery, development, and clinical adoption of pathogen-targeted antibiotics have been hampered by technical and regulatory challenges. Growing insights into bacterial physiology and mechanisms of resistance, innovative clinical trial designs, streamlined regulatory approval pathways, and availability of rapid bacterial diagnostics are recent developments that can help address those challenges. Pathogen-targeted antibiotics provide an opportunity to treat patients with the right drug at the right time, leading to improved patient outcomes and better antimicrobial stewardship. Patient-centered pricing and reimbursement reform is needed to incentivize innovation.

Neck injuries in football are attributed to helmet-to-helmet contact with youth players being at greatest risk. In 2014, the National Federation of State High School Associations (NFHS) implemented rules defining illegal contact against a defenseless player above the shoulders to reduce head and neck injuries in football players. This study evaluates whether rule implementation decreased rates of high school football neck injuries presenting to the emergency department (ED) pre-rule implementation (2009-2013) to post-rule implementation (2015-2019).Data were queried from the National Electronic Injury Surveillance System for high school football players 14 to 18 years old diagnosed with a neck injury from 1 January 2009 to 31 December 2019. Narratives in the data were reviewed for mechanism of injury, setting, loss of consciousness (LOC), and type of injury.Between 2009 and 2019, an estimated 47,577 high school football neck injuries were diagnosed in EDs across the United States. 52.0% of neck injuries were sustained during competition compared to 48.0% during practice. A statistically significant (This study is the first to identify a decrease in overall and helmet-to-helmet related neck injuries diagnosed in the ED following the 2014 NFHS targeting rule implementation. These findings add to the growing literature regarding the importance and efficacy of rule implementation in reducing sports-related neck injuries.

Background This study directly compares the recurrence rates of dorsal wrist ganglion cysts in patients treated via open surgical excision versus arthroscopic surgical excision. We hypothesized that there would be no difference between recurrence rates with these 2 surgical options. Methods We retrospectively reviewed the charts of all patients with a dorsal ganglion cyst undergoing either open or arthroscopic surgical excision at a single academic center with 3 fellowship-trained attending hand surgeons from 2012 to 2017. Charts were identified using Current Procedural Terminology codes and were reviewed using postoperative office notes for preoperative and postoperative symptoms, episodes of recurrence, time at which recurrence occurred, subsequent operations, and outcome at final follow-up. Results The charts of 172 patients undergoing either arthroscopic or open dorsal ganglion excision were reviewed. Nine of 54 (16.7%) arthroscopic excisions resulted in cyst recurrence, while 8 of 118 (6.8%) open excisions resulted in cyst recurrence ( P = .044). Two of 9 (22%) recurrences after arthroscopic ganglion excision versus 2 of 8 (25%) recurrences after open ganglion excision underwent repeat surgical intervention. Time to recurrence, as well as final follow-up, was not statistically different between groups. Conclusions Dorsal wrist ganglion cysts are the most common benign soft tissue mass of the upper extremity, but it remains unknown whether arthroscopic or open surgical excision leads to lower recurrence rate. Scant literature exists directly comparing these 2 methods of surgical excision. This study suggests that open excision of dorsal wrist ganglia leads to a lower recurrence rate than does arthroscopic excision.

Matthew W Konigsberg, John D Mueller, Jordan A Lebovic, R Kumar Kadiyala Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY, USACorrespondence: Matthew W KonigsbergDepartment of Orthopedic Surgery, Columbia University Medical Center, 622 W. 168th St. 11th Floor, New York, NY 10032, USATel +1-212-305-5976Fax +1-212-305-6193Email Mk3294@cumc.columbia.eduIntroduction: The purpose of this study was to describe four cases of patients who developed concomitant upper extremity and gluteal compartment syndrome in the context of substance abuse. In somnolent patients unable to provide a reliable physical exam, the healthcare provider must be aware of patients presenting with concomitant upper extremity and gluteal compartment syndrome.Methods: Retrospective chart review identified cases of the combined upper extremity and gluteal compartment syndrome following illicit drug abuse at a single academic center during the years 2009– 2019.Results: During the 11-year period examined, a total of eight patients were diagnosed with compartment syndrome secondary to illicit drug use and prolonged immobilization. Four (50%) patients presented with combined upper extremity and gluteal compartment syndrome. All of these patients underwent prompt surgical release of the affected compartments. All eventually returned to normal activities of daily living.Discussion: Compartment syndrome is primarily a clinical diagnosis, with physical exam being extremely important. In patients presenting with somnolence secondary to illicit drug use, physical exam may not be reliable. It is critical to have a high clinical suspicion in this patient population, understanding that these patients may present with concomitant upper extremity and gluteal compartment syndrome.Level of Evidence: Level IV, case series.Keywords: compartment syndrome, fasciotomy, trauma, upper extremity, gluteal

Aims Medical comorbidities are a critical factor in the decision-making process for operative management and risk-stratification. The Hierarchical Condition Categories (HCC) risk adjustment model is a powerful measure of illness severity for patients treated by surgeons. The HCC is utilized by Medicare to predict medical expenditure risk and to reimburse physicians accordingly. HCC weighs comorbidities differently to calculate risk. This study determines the prevalence of medical comorbidities and the average HCC score in Medicare patients being evaluated by neurosurgeons and orthopaedic surgeon, as well as a subset of academic spine surgeons within both specialities, in the USA. Methods The Medicare Provider Utilization and Payment Database, which is based on data from the Centers for Medicare and Medicaid Services’ National Claims History Standard Analytic Files, was analyzed for this study. Every surgeon who submitted a valid Medicare Part B non-institutional claim during the 2013 calendar year was included in this study. This database was queried for medical comorbidities and HCC scores of each patient who had, at minimum, a single office visit with a surgeon. This data included 21,204 orthopaedic surgeons and 4,372 neurosurgeons across 54 states/territories in the USA. Results Orthopaedic surgeons evaluated patients with a mean HCC of 1.21, while neurosurgeons evaluated patients with a mean HCC of 1.34 (p < 0.05). The rates of specific comorbidities in patients seen by orthopaedic surgeons/neurosurgeons is as follows: Ischemic heart disease (35%/39%), diabetes (31%/33%), depression (23%/31%), chronic kidney disease (19%/23%), and heart failure (17%/19%). Conclusion Nationally, comorbidity rate and HCC value for these Medicare patients are higher than national averages for the US population, with ischemic heart disease being six-times higher, diabetes two-times higher, depression three- to four-times higher, chronic kidney disease three-times higher, and heart failure nine-times higher among patients evaluated by orthopaedic surgeons and neurosurgeons. Cite this article: Bone Joint Open 2020;1-6:257–260.

Background: Total shoulder arthroplasty (TSA) is an increasingly common procedure. This study looked at trends in TSA using a nationwide registry, with a focus on patient demographics, comorbidities, and complications. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent TSA from 2005 to 2018. Cohorts were created based on year of surgery: 2005-2010 (N = 1116), 2011-2014 (N = 5920), and 2015-2018 (N = 16,717). Patient demographics, comorbidities, operative time, hospital length of stay, discharge location, and complications within 30 days of surgery were compared between cohorts using bivariate and multivariate analysis. Results: Bivariate analysis revealed significantly more comorbidities among patients in the 2015-2018 cohort compared with the 2005-2010 cohort, specifically American Society of Anesthesiologist class III or IV (57.0% vs. 44.3%, P < .001), morbid obesity (10.8% vs. 7.8%, P < .001), diabetes (17.8% vs. 12.1%, P < .001), and chronic obstructive pulmonary disease (6.7% vs. 4.1%, P = .003). The use of regional anesthesia has decreased (5.6% in 2005-2010 vs. 2.8% in 2015-2018, P < .001), as has operative time (▵: −16 minutes, P < .001) and length of stay (▵: −0.6 days, P < .001). There were also significant decreased rates of perioperative blood transfusion (OR [odds ratio], 0.46), non-home discharge (OR, 0.79), urinary tract infection (OR, 0.47), and sepsis (OR, 0.17), (P < .001 for all comparisons) between the 2005-2010 and 2015-2018 cohorts. Conclusions: Between 2005 and 2018, patients undergoing TSA had increasingly more comorbidities but experienced lower rates of short-term complications, in the context of shorter hospitalizations and more frequent discharge to home.

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae. To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin at 2 g (therapeutic), zoliflodacin at 4 g (supratherapeutic), placebo, and moxifloxacin at 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia's formula (QTcF). At each time point up to 24 h after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1 to 4 h after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, electrocardiogram (ECG) morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well tolerated. These findings suggest that zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT03613649.).

Study Design Retrospective cohort. Objectives Identify the effectiveness of vertebral body stapling (VBS) in children with idiopathic scoliosis. Summary of Background Data VBS has been proposed as an alternative to bracing moderate curves in patients with adolescent idiopathic scoliosis (AIS) although a clear picture of comparative efficacy and safety remains to be established. Methods Ten skeletally immature patients with AIS and curves between 25° and 35° underwent anterior VBS by a single surgeon from 2008 to 2018. Indications included strong family history, high ScoliScore, curve progression despite bracing, or as an alternative for patients/families refusing bracing. Patients with thoracic kyphosis greater than 40°, curvature with a level above T4 or below L4, and double major curves were contraindicated. Patients with hybrid surgical plans or those who failed to reach skeletal maturity were excluded. Age, gender, levels stapled, pre- and postoperative radiographs, and incidence of secondary surgical intervention were evaluated. Outcomes were also compared with untreated and braced subjects from the BrAIST study. Results Ten patients met the inclusion criteria. Average age at VBS was 11.8 (9.7–13.5) with an average major Cobb angle of 30.9° (26°–35°). Average duration of follow-up was 6.4 years. All patients demonstrated curve correction at their first postoperative visit. At final follow-up, 50% of patients experienced curve progression greater than 5°, whereas the remaining 50% either remained stable or corrected over time. The five patients whose curves progressed underwent VBS at a significantly younger age (10.8 vs. 12.8; p value .003). Four of these patients required additional surgical intervention for worsening scoliosis. Conclusions Although early outcomes after VBS appear to parallel the results of bracing, stapling does not affect the percentage of patients ultimately requiring PSIF. Initial curve correction degraded over time in younger patients with significant growth remaining, and high rates of progression in this group, even with bracing, merits investigation into more efficacious treatment strategies. Level of Evidence Level III.

Background: Injury to the ulnar collateral ligament of the elbow is common among overhead throwing athletes and can result in significant functional limitations. While surgical reconstruction offers high rates of return to competition, there are no validated or universally accepted guidelines for determining when an athlete can safely resume play. Purpose: To assess the existing scientific literature for return-to-competition criteria utilized after ulnar collateral ligament reconstruction. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: The PubMed database was searched for clinical investigations of ulnar collateral ligament reconstruction in overhead throwing athletes published between January 2000 and June 2020. Only studies that had a minimum follow-up of 1 year and included at least 1 specific return-to-competition criterion were considered. Results: A total of 15 studies were included in the final analysis, encompassing 1156 patients with an average age of 20.7 years (SD, 2.0 years). Baseball players composed 96.3% of patients for whom sport was specified, and 92.4% of baseball players were pitchers. The most common return-to-competition criterion, identified in 87% of studies, was completion of a return-to-throwing program, which started on average 16.7 weeks (range, 12-18 weeks) after surgery. A return-to-mound program was utilized in 53% of studies, starting on average 7.4 months (range, 6-9 months) postoperatively. Minimum time from surgery was used in 73% studies, with players waiting 7 to 12 months (mean, 9.7; SD, 1.4 months) after surgery before return-to-competition consideration. The overall rate of return to competition at the preinjury level or higher was 85.7% (SD, 8.5%) at an average of 12.2 months (SD, 0.6 months). Conclusion: In general, we observed a paucity of literature describing the return-to-competition process after ulnar collateral ligament reconstruction in overhead throwing athletes. Only 3 explicit return-to-competition criteria were identified across all studies: completion of a return-to-throwing program, completion of a return-to-mound program for pitchers, and minimum time from surgery. Increased transparency regarding postoperative rehabilitation protocols and further research are necessary to identify and validate sport-specific return-to-competition criteria, which will ultimately help athletes return to play in a safe and timely fashion after ulnar collateral ligament reconstruction.

Background: Concussions occur at higher rates in high school football as compared with all other high school sports. In 2014, the National Federation of State High School Associations implemented rules defining illegal contact against a defenseless player above the shoulders to reduce concussions in football players in the United States. To the best of our knowledge, rates of emergency department (ED)—diagnosed concussions of high school football players before and after the 2014 rule implementation have not been compared. Hypothesis: It was hypothesized that (1) there would be lower rates of helmet-to-helmet and helmet-to-body-part concussions after rule implementation and (2) alternative mechanisms of concussion would not differ, as these would be less influenced by rule implementation. Study Design: Cohort study; Level of evidence, 3. Methods: Data from the National Electronic Injury Surveillance System (NEISS) were analyzed for high school football players 14 to 18 years old sustaining a concussion from January 1, 2009, to December 31, 2019. Data were collected on mechanism of injury, setting, and loss of consciousness. Raw data were used to calculate national estimates based on the assigned statistical sample weight of each hospital by the NEISS. Results: A total of 4983 (national estimate = 154,221) high school football concussions were diagnosed in US EDs; 58.8% of concussions occurred during competition and 41.2% during practice. Between 2009 and 2013 the rate of concussions diagnosed in EDs rose 10.7% as compared with a 6.2% decrease between 2015 and 2019 ( P = .04). Between 2009 and 2013, the rate of helmet-to-helmet concussions rose 17.6% as compared with a 5.6% decrease between 2015 and 2019 ( P = .03). There were no significant changes between other mechanisms of concussion before and after the 2014 rule implementation. Conclusion: We identified a decreased trend in overall and helmet-to-helmet high school football concussions diagnosed in the ED after implementation of the targeting rule. This study adds to the growing literature regarding the importance and efficacy of rule implementation in reducing sports-related concussions.

Background: Controversy exists over the ability of various lumbar interbody fusion techniques to realign global and regional balance and their effect on patient outcomes. This is a retrospective cohort study to compare thirty-day postoperative outcomes between anterior and posterior interbody fusion techniques within a large national database. Methods: A retrospective cohort study utilizing the NSQIP database included 2,372 (29.9%) single-level anterior/direct lateral interbody fusions (ALIF/DLIF) and 5,563 (70.1%) single-level posterior/transforaminal interbody fusions (PLIF/TLIF) between 2013 and 2014. Emergent cases, fracture cases, and preoperative compromised wounds were not analyzed. Primary thirty-day outcomes included mortality, return to operating room, readmission, length of stay, and other major complications. Minor outcomes included urinary tract infection, superficial incisional site infection, and perioperative blood transfusion within 72 hours. Results: ALIF/DLIF was performed more for degenerative lumbar disc disease (31.0% vs . 13.9%, P vs . 24.4%, P vs . 0.1%, P=0.021) in the univariate analysis and persisted in the multivariate analysis (OR =12.8; 95% CI, 1.37–119.6; P=0.025). Significantly more PLIF/TLIF patients required blood transfusions within 72 hours of surgery (9.6% vs . 7.6%, P=0.005). This difference did not persist in the multivariate analysis after controlling for covariates. Elevated ASA physical status classification, age >60, prior bleeding disorder, and preoperative anemia were significantly associated with blood transfusion requirement. More deep venous thrombosis occurred (DVT) with ALIF/DLIF compared to PLIF/TLIF (1.0% vs . 0.6%, P=0.025), which persisted in the multivariate analysis (OR =2.03; 95% CI, 1.13–3.65; P=0.017). Conclusions: Although numerous techniques can be utilized in the treatment approach to various lumbar pathologies, anterior approaches have an increased risk of developing a perioperative DVT and early mortality. Transfusion risk is more strongly associated with elevated ASA class, increased age, preoperative anemia, and patients with bleeding disorders.

Background: Given the increasing societal focus on health care utilization and value-based care, it is essential to understand the demographic and economic data surrounding percutaneous vertebral augmentation procedures performed in the United States. Double-blinded prospective randomized controlled trials have shown no benefit to the use of vertebroplasty over a sham procedure in the treatment of vertebral fractures. Contrastingly, kyphoplasty may be beneficial when appropriately indicated. Methods: The National Inpatient Sample (NIS) database was queried for patients who underwent either kyphoplasty (ICD-9-CM 81.66) or vertebroplasty (ICD-9-CM 81.65) procedures between 2006 and 2014 across 44 states. Demographic and economic data were obtained which included the annual number of surgeries, age, sex, insurance type, location, and frequency of routine discharge. The NIS database represents a 20% sample of discharges from U.S. hospitals, which is weighted to provide national estimates. Results: In 2014, an estimated total number of 19,420 kyphoplasty and 6,130 vertebroplasty procedures were performed across the United States. The number of vertebroplasty procedures decreased 53% from 13,128 in 2008. Similarly, the number of kyphoplasty procedures decreased 17% from 23,320 in 2007. Based on payer, Medicare patients comprised 83% of those billed for kyphoplasty and vertebroplasty, and 75% of procedures were utilized in areas designated as “not low income”. In 2014, patients in the South Atlantic region comprised 24% of vertebroplasty and 28% of kyphoplasty cases, far more than any other region. Additionally, kyphoplasty and vertebroplasty were more often performed in teaching facilities rather than community hospitals (60% and 67%, respectively). Conclusions: Since the publication of two double-blind, prospective randomized controlled trials showed no benefit of vertebroplasty over a sham procedure, there has been a significant decrease in both kyphoplasty and vertebroplasty procedures.

Objectives: No model exists to predict which patients with elbow ulnar collateral ligament (UCL) injuries will successfully return to play (RTP) with non-operative treatment. The reported rates for successful RTP after non-operative management of UCL injuries are limited and vary widely. Furthermore, patient and UCL injury characteristics that influence failure of non-operative treatment have not been established. We sought to identify which factors were most significant in predicting which patients would have successful RTP after non-operative management of UCL injury. In doing so, we created the Elbow UCL Injury Prognosis Score to identify and weigh factors that predict failure of non-operative treatment. The parameters include: age, position, competition level, moving valgus stress test (MVST), 5th finger sensation, UCL tenderness, and MRI findings including tear type, location, and chronicity features. This score will predict which patients will succeed non-operative management, avoiding unnecessary surgery while simultaneously identify patients for whom non-operative management would be delaying the inevitable need for surgical intervention. Methods: 205 patients were evaluated by the senior author for a UCL injury. Physical exam findings, imaging characteristics and patient demographics were retrospectively collected and entered into a HIPAA-compliant REDCap database after IRB approval of the study design. Of these patients, 138 underwent a trial of non-operative treatment and were either cleared for RTP (n= 55) or eventually underwent surgical intervention (n= 83) after a minimum one-month trial of non-operative management. Sixty-seven patients decided to have surgery immediately without trialing non-operative management and were excluded from the scoring system. The Elbow UCL Injury Prognosis Score was developed and validated using stepwise feature selection by Akaike information criterion (AIC). Three-fold cross validation was performed using these ten variables as predictors. The mean and standard deviation of area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value were evaluated. Results: The area under curve for non-operative failure predicting non-operative management failure was 0.79 (0.054), with sensitivity=0.85 (0.088), specificity=0.72 (0.032), positive predictive value=0.83 (0.023), negative predictive value=0.77 (0.091) [mean (standard deviation (SD))]. Patients were predicted to succeed non-operative management if they scored less than 10, while for a score greater than or equal to 10 patients would likely fail non-operative management and require surgical intervention for their UCL injury (Table 1). Conclusion: The Elbow UCL Injury Prognosis Score is a statistically rigorous, powerful tool for predicting which patients will most likely RTP with non-operative treatment. We hope this score can provide surgeons with a useful tool to enhance and enable shared decision making with patients when faced with UCL injuries at all competitive levels. [Table: see text]

Researchers examined the perspectives of 274 senior housing officers and 283 graduate students on the declining number of resident director candidates. Data from two separate surveys indicated that quality of life, remuneration, and interest in the residence life profession were significant issues. Implications for professional preparation, practice and research are explored.

Quality of Life and PFT values from pediatric Spinal Muscular Atrophy (SMA) patients post-VEPTR implantation were evaluated. There was improvement in pulmonary function assessed by patient-reported outcomes measured at 1 year and 2 years postoperatively.

A portable solid-state recorder-display system was used to measure and analyze heart rate during the waking hours of 3 consecutive days in free-living sedentary normal middle-aged men who were randomized to undergo 3 regimens of physical activity during a 12-week period: low-intensity exercise training at home (n = 21), high-intensity exercise training at home (n = 23) and customary activity (n = 20). This was done to determine whether the system could detect changes in heart rate and, indirectly, in physical activity within the 3 groups. In both training groups the percentage of total recorded time spent within the prescribed high or low heart rate range recorded at 6 or 12 weeks increased significantly (p less than 0.05), whereas control subjects showed no increase above baseline values. Peak oxygen consumption increased by 8% and 17% in men undergoing low- and high-intensity training, whereas in control subjects it did not change. This solid-state system reliably measures prescribed increases in heart rate and provides an indirect measure of physical activity in normal sedentary men undergoing exercise training at home.

1 . The patient described in this report had macrocytic anemia, megaloblastic maturation arrest in the bone marrow, glossitis, hyper-reflexia and diminished vibration perception in the feet. None of these abnormalities was improved by liver extract or vitamin B12 but all responded rapidly to folic acid except the neurologic signs. 2. This patient appears to have had a megaloblastic anemia which has been described in European clinics under the names "achrestic anemia" and "refractory megaloblastic anemia." It appears to be similar to "Wills" factor deficiency anemia" and some cases of pernicious anemia of pregnancy. 3. This patient did not appear to have a primary deficiency of folic acid since the excretion of this substance in the urine was within normal limits. A deficiency of an unknown factor probably equivalent to "the Wills’ factor" is suggested. 4. It seems likely that folic acid induced a remission in this case by a "mass action" effect. The possible relationship of folic acid, vitamin B12, the unknown factor and liver extract to nucleo-protein synthesis is discussed.

Obesity and elevated serum lipids are among the risk factors for vascular disease and atherosclerosis. Thus, the dietary approach to the problem cannot be ignored.

There is evidence in the literature that the conversion of tryptophan to N1-methylnicotinamide may require pyridoxine (1,2,3). Holt (4) has suggested that a reduction in the amount of N’-methylnicotinamide excreted after a test dose of tryptophan may be used as a test for pyridoxine deficiency. Other evidence has been reported (5,6), however, that pyridoxine is not a factor of primary importance in the conversion and that the apparent relationship between pyridoxine deficiency and poor conversion of tryptophan to N’-methylnicotinamide is due to severe caloric restriction (6) or protein imbalance (7,8). Heimberg, Rosen, Leder, and Perlzweig (9) have shown that the protein level of the diet is of primary importance to the amount of N’-methylnicotinamide excreted, after test doses of tryptophan; the higher the protein level the lower the amount of N1-methylnicotinamide. They found no evidence to support a primary need for pyridoxine in this conversion, though at a 10% casein level, pyridoxine deprivation induced a reduction in the amount of N’-methylnicotinamide excreted. Using desoxypyridoxine, a pyridoxine antagonist, we have produced what appears to be pyridoxine deficiency in human beings (10). Seborrhea-like dermatitis and mucous membrane lesions are induced which respond to pyridoxine but not to other members of the vitamin B com

1. The hematologic syndrome called refractory anemia with hyperplastic bone marrow, aregenerative anemia, chronic bone marrow failure, pseudo-aplastic anemia, and many other terms, has been separated into five types on the basis of clinical and hematologic studies on 23 patients carried out over a period of 16 years. These groupings are probably highly artificial but are made to facilitate presentation and description. As more is learned of the chemistry of the bone marrow cells in patients with refractory anemia, a more satisfactory classification will be possible. 2. Type 1 is characterized by bizarre chromatin in the normoblasts, mast cell hyperplasia, hemosiderosis or hemochromatosis and a tendency for spontaneous remissions to occur. 3. Type 2 is at first typified by complete or almost complete erythroid aplasia. Hyperplasia of erythroid cells with maturation arrest and bizarre chromatin pattern may occur later, and finally spontaneous remission may appear with considerable frequency. Mast cell hyperplasia, thymoma and hemosiderosis have been noted. 4. Type 3, associated with exogenous toxins and the preleukemia state, is characterized by pancytopenia and a bizarre chromatin pattern in the normoblasts. Some of these patients may he classified as "DiGuglielmo syndrome." 5. Type 4 also is typified by pancytopenia and hyperplasia of bone marrow but with cells of normal appearance. These patients responded partially or completely when splenectomy was performed, and probably represent a variant of the "hypersplenism" syndrome. 6. Type 5 is refractory megaloblastic anemia with typical cytologic changes evident in all cell types similar to those found in pernicious anemia. 7. Hypotheses are proposed to explain these various types of anemia on the basis of abnormalities in the metabolism of nucleic acids, particularly DNA. Deficiencies of metabolites, inhibition of metabolic reactions by exogenous or endogenous toxins, or by immune mechanism in which DNA serves as haptene, are possible explanations.

1. Patients with pernicious anemia who are maintained on folic acid, 30 mg. three times a week, for two to three years may have a hematologic relapse which will remit satisfactorily if refined liver extract is given, or partially if the dose of folic acid is increased to 50 mg. daily, or if thymine is given. 2. The hematologic remission succeeding the increased dosage of folic acid is followed within several months by a second relapse. At this time the response of these patients to liver extract or vitamin B12 is retarded. Recovery occurs after two to four months. 3. These experiments suggest that folic acid exerts its effect by "mass action" in pernicious anemia and that it is essential to the formation of thymine and other pyrimidines and purines or facilitates the utilization of these substances. 4. Posterolateral column disease or peripheral neuritis occurred in every person with pernicious anemia who received increasing doses of folic acid to maintain an hematologic remission. This observation suggests that folic acid, by pushing a chemical reaction through to completion in the face of a serious deficiency of vitamin B12, depleted the supply of this factor even more and led to the development of combined system disease. 5. Uracil produced a hematologic response in 2 of 3 persons with pernicious anemia in relapse when given in doses of 15-30 grams daily. The data suggest that uracil may be a precursor of thymine. 6. A patient with pernicious anemia of pregnancy failed to respond to uracil, 30 grams daily, but did respond partially when choline, 3 grams, and methionine, 6 grams were given. Thymine induced a complete response. The partial response to methionine and choline and the better response to thymine suggest that choline and methionine supplied methyl groups for the formation of thymine, but that activating substances for the methylating process were missing. 7. Reference is made to a patient previously reported from this laboratory who had liver extract and vitamin B12-refractory megaloblastic anemia but who responded to folic acid and on a second relapse to thymine. Studies on the output of folic acid in the urine of this patient did not support the possibility of folic acid deficiency, and the suggestion was made that another substance, possibly the "Wills’ factor," was deficient, and that this factor together with folic acid activated the formation of thymine. These two factors correspond to the activators of the transmethylation reaction mentioned in the preceding paragraph. 8. These studies on human beings and similar ones in bacterial metabolism suggest that folic acid, liver extract and vitamin B12 are essential to the formation of nucleic acid and nucleoprotein through a chemical chain reaction. The suggestion is made that the megaloblast common to pernicious anemia and related macrocytic anemias is a primitive erythroblast with an abnormality in the metabolism of nucleoprotein. The so-called maturation arrest in all marrow elements occurs because of this abnormality which may be induced by a deficiency of vitamin B12, folic acid, the "Wills’ factor," and probably other chemical activators of this reaction.

SummarySubcutaneous adipose tissue was obtained from 8 patients undergoing various surgical procedures. All were in good nutritional balance. In each instance it was possible to demonstrate considerable lipolytic activity in vitro in the fatty tissue. It was further possible to identify this hydrolytic enzyme as lipoprotein lipase, similar in its characteristics to that previously reported in animal blood and tissue and human blood.

As a result of intense interest, supported by many clinical examples, a large body of knowledge concerning the interactions of drugs is being assembled which has very practical impacts on patient care. In part, such information has been abetted by the rapidly evolving methodology utilized by the clinical pharmacologist in studies on drug absorption, metabolism, and excretion. It has also received impetus from the increasing appreciation of the frequency of iatrogenically, drug-induced diseases in clinical practice. Thus, when one considers the essentiality of dietary nutrients for the innumerable and complex physiologic functions of the body, in both the healthy and the diseased state, including those specifically related to drug metabolism, it is not surprising that considerable interest has developed in drug-nutrient interrelationships. This has been evidenced by several recent symposia, review articles, and books (Miller, 1976; Roe, 1976; Hartshorn, 1977; Hathcock and Coon, 1978).

and his family. Recent estimates of the number of persons suffering from alcoholism and alcohol abuse in the United States place the figure at approximately 9 million.1 Further, it can be assumed that every alcoholic ad versely affects the mental health of two or three family members, thus adding another 20 to 30 million persons who feel the de structive impact of the illness. The cause of alcoholism is not known.

Publisher Summary This chapter discusses the conflicting data on the relationship of the vitamin B 6 group, especially pyridoxine, to only a few of the many aspects of fat metabolism. The fatty acid composition of adipose tissue of pyridoxine-deficient rats is different from normals and that injections of insulin tended to reverse these changes. Pyridoxine-deficient rat serum and pancreatic tissue had lowered levels of insulin as measured by the epididymal fat pad method for insulin-like activity. Such evidence suggests that the lipid changes in pyridoxine-deficient rats might be related to the more complex relations of insulin insufficiency to fat metabolism. Indirect pathway is suggested by which fat metabolism can affect the utilization of vitamin B 6 and vice versa. The chapter mentions the known relationships between phospholipids and cholesterol esters on the one hand and fatty acid transport on the other.

ministration of Lipomul#{174} IV. (Upjohn) in man have virtually disappeared, continuous multiple infusion therapy has been associated with a severe reaction, sometimes called the ‘ ‘over-loading syndrome, ‘ ‘ but better referred to as the long-term 3 The latter is characterized by the abrupt onset of fever, hepatosplenomegaly, anemia and hemorrhagic manifestations. It may develop at any time, even several days after completion of the series, but never before at least the twelfth infusion, and more frequently after sixteen or more. Although one or all the features of the syndrome may be present in any one patient, the anemia arid hemorrhagic complications are the most striking and lifethreatening. The incidence of these reactions is difficult to ascertain, since most investigators have been rightly unwilling to explore the regularity of occurrence for ethical reasons. Since a similar syndrome cannot be produced in animals with comparable dosage schedules, we may never know its true incidence. Nonetheless, it should be noted that many patients can be given extremely large quantities of the emulsion without ever having any serious complications. However, regardless of incidence, the threat of such a reaction precludes general acceptance of Lipomul IV. except for shortterm administration.

Summary1. Purified, unagglutinated platelet suspensions prepared from rabbit blood do incorporate radioactive phosphorus readily, and therefore lend themselves to life span studies in vivo. 2. These studies indicate that transfused rabbit radioactive platelets are rapidly removed from the peripheral blood and the radioactivity recovered in organs of the reticuloendothelial system, namely spleen, liver, lung and bone marrow. 3. The problem of viability of these platelets is discussed. The evidence suggests that damage has occurred during manipulation. 4. These observations are important primarily in demonstrating aspects of metabolism and destruction of platelets.

Summary1. The production of pyridoxine deficiency in adrenalectomized mice calls forth the same hematologic response, neutrophilia and lymphopenia, as in intact animals. This is positive evidence that these blood changes occurring in pyridoxine deficiency are not the result of an alarm reaction mediated through the adrenal gland. (2) Pyridoxine deficiency and cortisone administration produce similar hematologic responses. When combined, a synergistic effect results. This may be evidence that the mechanism of the production of the hematologic changes is different in the 2 conditions. (3) Further evidence that the mechanisms may differ is the fact that the cortisone effect cannot be blocked by giving large amounts of pyridoxine, pyridoxal, and pyridoxamine, although the possibility exists that cortisone has a role at another site in the B6 cycle.

"The thing I hate about working with the alcoholic is that you get him all patched up and send him home, and the next thing you know he's readmitted in the same shape. What's the use?" Such statements typify many health workers' reactions. In one sense, the response is understandable. In an era of wonder drugs, refined surgical techniques, early ambulation, and rapid discharge, we are conditioned to expect rapid and relatively certain recovery from many illnesses. Unfortunately, the "magic pill" for alcoholism has not been found. Our reactions are further shaped by our culture's long-held view of the alcoholic as a weak, irresponsible lush. In spite of growing sophistication that leads us to affirm that alcoholism is an illness, a sizable gap separates this intellectual awareness from gut-level acceptance of it. It is generally acknowledged within the field that there are 6 to 9 million alcoholics in this country. Only about 5 percent match the popular stereotype, the Skid Row drunk. According to the World Health Organization the United States has the highest rate of alcoholism. The illness ranks as the third or fourth