Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics.

Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002).

Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects.

Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

Measurement of head impacts in youth ice hockey players.

Despite growing interest in the biomechanical mechanisms of sports-related concussion, ice hockey and the youth sport population has not been studied extensively. The purpose of this pilot study was: 1) to describe the biomechanical measures of head impacts in youth minor ice hockey players; and, 2) to investigate the influence of player and game characteristics on the number and magnitude of head impacts. Data was collected from 13 players from a single competitive Bantam boy's (ages 13-14 years) AAA ice hockey team using telemetric accelerometers implanted within the players' helmets at 27 ice hockey games. The average linear acceleration, rotational acceleration, Gadd Severity Index and Head Injury Criterion of head impacts were recorded. A significantly higher number of head impacts per player per game were found for wingers when compared to centre and defense player positions (df=355, t=3.087, p=0.00218) and for tournament games when compared to regular season and playoff games (df=355, t=2.641, p=0.086). A significant difference in rotational acceleration according to player position (F2,1812=4.9551, p=0.0071) was found. This study is an initial step towards a greater understanding of head impacts in youth ice hockey.

Perioperative Mortality Does Not Explain Racial Disparities in Gastrointestinal Cancer.

BACKGROUND: Racial minorities with gastrointestinal cancer suffer disproportionately poor overall and disease-specific survival. We used a nationally representative sample to examine the relationship between race/ethnicity and mortality and determine whether these disparities were observed in the perioperative period. MATERIALS AND METHODS: The Nationwide Inpatient Sample (NIS) was used to examine patients undergoing surgery for cancers of the esophagus, stomach, pancreas, colon and rectum ("GI cancer") between 2008 and 2012. Logistic regression was used to evaluate whether race/ethnicity was associated with perioperative mortality after adjusting for sociodemographic characteristics, perioperative factors and presentation (ER vs elective). RESULTS: A total of 110,044 subjects were identified, including 75.8% Whites, 10.5% Black patients, 7.2% Hispanic patients, and 3.1% Asian/Pacific Islanders (API). Whites were generally older than minorities. In adjusted multivariable generalized linear mixed logistic models, no increase in perioperative mortality was seen for minorities. Worse outcomes were observed for those with higher Elixhauser comorbidity score (OR 6.90, CI 5.96-7.99), lower income region (OR 1.24, CI 1.10-1.40), males (OR 1.54, CI 1.42-1.68), and those without private insurance (Medicare OR 1.34, CI 1.16-1.55; Medicaid OR 1.27, CI 1.02-1.58; self-pay OR 1.64, CI 1.24-2.17). Differences in mortality were predominantly driven by comorbidities (pseudo %ΔR2 = 38.56%) and only minimally by race (pseudo %ΔR2 = 0.49%). CONCLUSION: Minority groups do not suffer higher rates of perioperative mortality for GI cancer surgeries after controlling for clinical and demographic factors. Future work to address cancer disparities should focus on areas in the cancer care trajectory such as cancer screening, surveillance, socioeconomic factors, and access.

Salivary levels of anticonvulsants: a practical approach to drug monitoring.

Phenobarbital, phenytoin, carbamazepine, primidone, and ethosuximide were measured in saliva and plasma obtained simultaneoulsy from 115 patients. A method to correct for the effect of salivary pH on phenobarbital concentration of saliva was developed. Salivary concentrations of these drugs were found to be equivalent to the plasma free drug and to correlate closely with the total plasma levels. Expressed as percent of total plasma drug, the salivary (S) and plasma free (P) concentrations were: phenytoin, S 11.1 +/- 2.0 percent (mean +/- SD), P 10.1 +/- 2.4 percent (r = 0.97); carbamazepine, S 26.0 +/- 2.4 percent, P 25.9 +/- 3.4 percent (r = 0.97); phenobarbital, S 43.1 +/- 5.2 percent, P 40.8 +/- 7.9 percent (r = 0.91); primidone, S 75.4 +/- 24.9 percent, P 66.4 +/- 8.8 percent (r = 0.76). Ethosuximide was not bound by plasma proteins, and its plasma and salivary levels were equal.

Hypoproteinemic alkalosis.

Hypoproteinemia by itself causes a nonrespiratory ("metabolic") alkalosis. On the average, a decrease in plasma albumin concentration of 1 g/dl produces an increase in "standard" bicarbonate of 3.4 mM/liter, and an apparent base excess of +3.7 meq/liter; it also reduces the value of the normal anion gap by about 3 meq/liter. Concentration of plasma protein should be measured as part of the analysis of acid-base status. Interpretation of acid-base data requires special consideration in "primary hypoproteinemic alkalosis."

Malnutrition is associated with increased diarrhoea incidence and duration among children in an urban Brazilian slum.

This study was undertaken to further define the relationship between malnutrition and subsequent diarrhoeal illness among children. A cohort of 61 children under five years of age was followed for two years in an urban Brazilian slum. Nutritional status was determined at two-month intervals and was used to predict the subsequent occurrence of diarrhoea. A significant, graded association between worsened nutritional status, as measured by length- or weight-for-age, and diarrhoea incidence was found. This relationship was present for both two-month and one-year periods following nutritional assessment. The average duration of diarrhoea was also significantly longer during the two-month periods which were preceded by the worst nutritional status. Overall, the most malnourished children had nearly twice the total number of days of diarrhoea that better nourished children had. These results provide additional evidence that a significant association between malnutrition and both increased diarrhoea incidence and duration exists.

Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan.

For 4 days before surgical repair of a diverticulitic colovesical fistula and for 6 days after, a 63-year-old man was treated with 2 g of intravenous cefotetan disodium every 12 hours for associated urosepsis with bacteremia. Postoperatively, the patient followed a diet of intravenous nutrition only. Uneventful convalescence was interrupted by signs of sudden major blood loss, accompanied by prolonged prothrombin time. After stabilization with packed red blood cells, fresh plasma, crystalloids, and parenteral vitamin K, laparotomy revealed a huge intra-abdominal clot, which was evacuated. This case illustrates the risk of unexpected hypoprothrombinemia and hemorrhage in a cefotetan-treated surgical patient who demonstrated none of the usual comorbid conditions generally described in patients with antibiotic-induced hypoprothrombinemia. Like cefamandole nafate, cefoperazone sodium, moxalactam disodium, and other cephalosporins containing the methylthiotetrazole side chain, cefotetan appears to pose an unusual risk of major bleeding.

Diarrhea as a cause and an effect of malnutrition: diarrhea prevents catch-up growth and malnutrition increases diarrhea frequency and duration.

Diarrhea and malnutrition, alone or together, constitute major causes of morbidity and mortality among children throughout the tropical world. Data from northeast Brazil, taken with numerous other studies, clearly show that diarrhea is both a cause and an effect of malnutrition. Diarrheal illnesses impair weight as well as height gains, with the greatest effects being seen with recurrent illnesses, which reduce the critical catch-up growth that otherwise occurs after diarrheal illnesses or severe malnutrition. Malnutrition (whether assessed by impaired weight or height for age) leads to increased frequencies and durations of diarrheal illnesses, with a 37% increase in frequency and a 73% increase in duration accounting for a doubling of the diarrhea burden (days of diarrhea) in malnourished children. A multi-pronged approach focusing on those with prolonged diarrhea and severe malnutrition is suggested.

Seroepidemiologic study of Cryptosporidium infection in children from rural communities of Anhui, China and Fortaleza, Brazil.

A cluster-sampling, cross-sectional study was conducted for assessing the prevalence of Cryptosporidium infection in children less than 16 years of age from three villages, Dondian, Linshan, and Fuziyin, in rural Anhui in eastern China. Among 320 apparently healthy children less than 10 years of age from Dondian who had stool specimens collected, cryptosporidial oocysts were found in stools of three children from Dondian, and no positive specimens were found in 239 children studied from Linshan. In addition, a total of 610 serum samples from children in these three villages were tested for specific IgG antibody to Cryptosporidium with an enzyme-linked immunosorbent assay (ELISA) and the prevalence rates were 42.3%, 51.7%, and 57.5%, respectively, in Dondian, Linshan, and Fuziyin. Seroprevalence increased progressively with age. No detectable antibody was found in infants between two and six months of age, and seropositivity steadily increased after one year of age. Among 36 sera from adults 15-60 years of age without diarrheal illness in Huanglu villages of rural Chaohu, 50% (18 of 36) were positive. As expected, a good correlation was found in the specific IgG antibody between the paired serum specimens from 30 matched mother-neonates who showed transplacental transfer of IgG. However, little or no IgM antibody was seen in the neonates even though several mothers had a positive anticryptosporidial IgM enzyme-linked immunoassay result. Forty randomly selected serum samples from children less than four years of age in a similarly impoverished semiurban community in Fortaleza, Brazil, where the majority of households also have pit toilets and shared community water supplies and 172 serum samples from patients one month to 29 years of age admitted to the University of Virginia Hospital without diarrhea were also examined. In Fortaleza, almost all children acquired antibody by their second year of life, demonstrating the high prevalence of this infection. In rural Anhui, only about half the children were infected by 5-7 years of age. The overall prevalence rate (16.9%) of seropositivity among children and young adults in Virginia was much lower than in China and Brazil. These results indicate that cryptosporidial infection is ubiquitous, and is highly endemic in these impoverished communities. The difference between China and Brazil may reflect earlier weaning, hygiene practices, poorer water or sanitation, multiple siblings in family and geographic environment in Brazil.

The effects of magnesium supplementation on exercise performance.

PURPOSE: To determine the effects of magnesium (Mg2+) supplementation on performance and recovery in physically active women using the sensitive and recently advanced measure of ionic Mg2+ (iMg). METHODS: Participants (N = 121) were screened for [iMg] in plasma, with 44 (36.4%) exhibiting [iMg] below the normal range of 0.53-0.67 mmol.L-1 (4). Thirty-two subjects (21 +/- 3 yr) representing a broad range of [iMg] (0.54 +/- 0.04 mmol.L-1) completed the main 14-wk study. At baseline, participants submitted to a resting blood pressure measurement, and they completed both an anaerobic treadmill test and an incremental (aerobic) treadmill test. For the latter, values for workload, oxygen uptake, and heart rate were obtained at both anaerobic threshold and maximal effort. Blood samples for iMg, total serum Mg2+ (TMg), erythrocyte Mg2+ (EMg), Ca2+, K+, Na+, hemoglobin, hematocrit, lactate, and glucose were also collected pretest, and 4, 10, 30 min, and 24 h posttest. Subjects received 212 mg.d-1 Mg oxide or placebo in a double-blind fashion and were retested after 4 wk. After a 6-wk washout period, the testing was repeated with a treatment crossover. RESULTS: Ionic Mg2+ increased with Mg2+ treatment versus placebo (P < 0.05); however, performance and recovery indices were not significantly affected. CONCLUSION: Four weeks of 212 mg.d-1 Mg oxide supplementation improves resting [iMg] levels but not performance or recovery in physically active women.

Early excision of heterotopic ossification about the elbow followed by radiation therapy.

We reviewed the results, in eight patients, of excision of heterotopic ossification about the elbow performed three to ten months (average, seven months) after the initial injury and followed by radiation therapy to prevent recurrence. The etiology of the heterotopic ossification included a neurological (head or spinal cord) injury in five patients and a local injury (fracture or fracture-dislocation) of the elbow in three patients. The average preoperative arc of motion of the three joints that were capable of motion was 12 degrees (5, 10, and 20 degrees); the remaining five joints were fixed in an average of 56 degrees (range, 10 to 90 degrees) of flexion. All of the patients received a total dose of radiation of 1000 centigray, divided into five fractions. The radiation therapy was instituted on the first postoperative day, and at least three of the remaining four treatments were administered on consecutive days. Radiation therapy was not performed on the weekend, so the five fractions were administered over the course of seven days. At an average of forty-six months (range, twenty-five to seventy-two months), the arc of motion averaged 103 degrees, which compared favorably with the 121-degree arc of motion that had been attained intraoperatively. Two patients who had residual motor deficits in the involved extremity had an arc of motion of 50 and 70 degrees at the latest follow-up evaluation; those who had normal motor function fared considerably better, averaging 118 degrees of motion. There was no substantial recurrence of ossification either radiographically or that limited motion, and no complications attributable to the radiation therapy were noted. On the basis of this experience, it seems that the generally recommended twelve to eighteen-month delay between injury and excision, to allow for maturation of heterotopic bone and thus to lessen the likelihood of recurrence, may be eliminated. Additional studies are needed to define the relative risk of recurrence in the various clinical settings in which heterotopic ossification is seen and to determine whether radiation therapy is necessary to prevent recurrence after early excision in each of these instances.

Treatment of severely comminuted intra-articular fractures of the distal end of the radius by open reduction and combined internal and external fixation.

BACKGROUND: Severely comminuted AO type-C3 intra-articular fractures of the distal end of the radius are difficult to treat. Failure to achieve and maintain nearly anatomic restoration can result in pain, instability, and poor function. We report the results of a retrospective study of the use of a standard protocol of open reduction and combined internal and external fixation of these fractures. METHODS: Seventeen of twenty-five patients treated with the protocol were available for follow-up evaluation. Six had an AO type-C3.1 fracture; eight, type-C3.2; and three, type-C3.3. Eleven fractures required a dorsal buttress plate and/or a volar buttress plate, and eleven required bone-grafting. The mean time until the external fixator was removed was seven weeks. RESULTS: At a mean of thirty months postoperatively, the mean arc of flexion-extension was 72% of that on the uninjured side and the mean grip strength was 73% of that on the uninjured side. The mean articular step-off was 1 mm, the total articular incongruity (the gap plus the step-off) averaged 2 mm, and the radial length was restored to a mean of 11 mm. Thirteen patients had less than 3 mm of total articular incongruity. Arthritis was graded as none in three patients, mild in ten, moderate in three, and severe in one. According to the Gartland and Werley demerit-point system, ten of the patients had a good or excellent result. According to the modified Green and O'Brien clinical rating system, five had a good or excellent result. One patient had a fracture collapse requiring wrist fusion, one had reflex sympathetic dystrophy, and three had minor Kirschner-wire-related problems. Total articular incongruity immediately postoperatively had a moderately strong correlation with the outcome as assessed with both clinical rating systems (r = 0.70 and 0.74 for the Gartland and Werley system and the Green and O'Brien system, respectively; p<0.05). CONCLUSIONS: Open reduction and combined internal and external fixation of AO type-C3 fractures can restore radiographic parameters to nearly normal values, maintain reduction throughout the period of fracture-healing, and provide satisfactory functional results.

Compression plate arthrodesis of the elbow.

We reviewed 15 patients with an arthrodesis of the elbow using an AO compression-plate technique, after an average follow-up of 24 months. The most common indication was an open, infected high-energy injury with associated bone loss. Arthrodesis was successful in all but one patient in whom severe deep infection necessitated amputation. Eight patients were treated with the metal partly exposed in an infected wound. After removal of the metal, all wounds healed secondarily and none had clinical or radiographic signs of sepsis at latest review. Compression-plate arthrodesis of the elbow is a generally applicable method that can be used even in cases of severe bone loss. There appears to be greater certainty of union than with other techniques, and no increased risk of subsequent fracture.

Persistent diarrhea in northeast Brazil: etiologies and interactions with malnutrition.

With the improved control of acute diarrheal illness mortality with oral rehydration therapy, persistent diarrhea is now emerging as a major cause of childhood mortality in tropical developing areas like the impoverished populations in Brazil's Northeast. "Graveyard surveillance" in the rural community of Guaiuba in northeastern Brazil revealed fully half of the 70% diarrhea mortality was due to persistent diarrheal illnesses. Furthermore, 11% of 14 or more diarrheal illnesses per child per year in an urban slum in Fortaleza persisted beyond 14 days, a definition that clearly identified the high risk children for heavy diarrhea burdens. Not only did heavy diarrhea burdens ablate the key "catch-up" growth seen in severely malnourished children and in children following previous diarrheal illnesses, but malnutrition significantly predisposed children to a greater incidence and duration of diarrhea as well as a greater incidence of persistent diarrhea. Etiologic studies of 37 children presenting with persistent diarrhea to Hospital das Clinicas in Fortaleza revealed that Cryptosporidium (in 13%) and enteroadherent E. coli (36% with aggregative, 29% with diffuse and 13% with localized adherence to HEp-2 cells) were the predominant potential pathogens found in the stool or upper small bowel. These findings suggest that persistent diarrhea is emerging as an important health problem in Brazil's Northeast, that it identifies a high risk child for heavy diarrhea burdens, that important interactions occur with malnutrition and that Cryptosporidium and enteroadherent E. coli warrant further study as potential etiologies of this major cause of morbidity and mortality.

The upper extremity trauma patient.

Trauma patients are predominantly young men. Urban trauma patients frequently are uninsured, and often are victims of intentionally inflicted penetrating injury, usually caused by firearms. Substance use is a common underlying factor in both urban and rural trauma. This article introduces urban and rural patients. It discusses their past medical and social histories, which are required to help the decision-making process when treating these patients.

Forearm fixation.

The great majority of forearm fractures in adults are best treated by open reduction and internal fixation. Although alternative methods exist, plate fixation is favored by most surgeons. With strict attention to surgical detail, complication rates are low and early active function is possible. The treatment of high-energy, open fractures can include various techniques such as internal or external fixation. Refracture remains the greatest risk following hardware removal, which is not necessary for all patients.

Inflammatory and traumatic tendinopathies about the ulnar wrist.

Tendinopathy about the ulnar aspect of the wrist may involve either extensor or flexor structures and has a variety of causes. Although relatively less common than intra-articular pathology, disorders of these superficial structures must not be neglected when performing a physical examination of the ulnar wrist or developing a differential diagnosis for patients with ulnar wrist pain.

AIDS in the hand patient: the team approach.

Hand surgeons and therapists were faced with a new clinical entity in the 1980s with the emergence of hand and upper extremity infections in patients with AIDS and HIV disease. This entity has become a worldwide epidemic of vast proportions and has proven to be one of the major health concerns of the 1990s. It seems likely that treatment of patients with this devastating disease for hand infections or more routine upper extremity problems will become routine in the future. The reality of surgical treatment and hands-on rehabilitative therapy for patients with a life-threatening infectious disease has been a concern voiced publicly by very few health care professionals, yet discussed quietly among colleagues quite frequently. Our aim must be to provide the highest quality of health care to this group of hand patients, just as we do for all other patients, while at the same time providing the safest possible environment for all members of the health care team. It appears that there is a higher incidence of HIV infection among hand patients than is noted in the general public; therefore, the hand surgeon and medical team should pay particular attention to the rapidly advancing front of new information available regarding care for this challenging group of patients. Hand surgeons and therapists are entering the 1990s armed with a wealth of new and valuable information about HIV disease that has been produced by intensive basic science research and clinical observations accumulated over the last 10 years. The fears generated by the initial misinformation and lack of information concerning modes of transmission of HIV have generally been supplanted by a more rational approach to patient care, fostered by the more accurate scientific information currently becoming available. Unfortunately, the rational approach to the HIV-related political and socioeconomic issues has not yet overtaken the discrimination and stereotyping of the populace stricken with HIV disease. It remains the responsibility of the medical community to continue research efforts aimed at delineating the clinical deficiencies manifested by these patients and determining their effects on treatment regimens for both the unique and commonplace medical and orthopedic problems noted in this patient population.