Protein dynamics and the immunological evolution of molecular recognition

While it is accepted that protein flexibility plays a role in protein folding, catalysis, and molecular recognition, few techniques are capable of the rigorous measurement of protein motions required to quantify flexibility. Three-pulse photon echo shift spectroscopy can be used to measure the time scale of protein motions, and we have used this technique, along with steady-state spectroscopy and binding and structural data, to examine the immunological evolution of protein flexibility in an anti-fluorescein antibody. Two light chain somatic mutations increase affinity for fluorescein by 12-fold but also significantly affect flexibility. Specifically, a rigidification of the protein is seen in each of three observable motions; two slower motions undergo decreased amplitudes of displacement, by 3- and 20-fold, respectively, in response to an applied force, and the distribution associated with the amplitude of a faster motion is narrowed upon somatic mutation. The somatic mutations appear to rigidify the antibody-fluorescein complex by more strongly anchoring fluorescein to the protein and by more tightly packing the complex. The data demonstrate that in addition to affinity, antibody dynamics are systematically manipulated during affinity maturation, and they imply that the evolution of protein flexibility may be a central component of the immune response. The results also reflect the type of protein rigidification that may be important for other biological interactions, such as protein-protein, protein-ligand or protein-drug, and enzyme-substrate recognition.     

Comparative study of the in-hospital case-fatality rate of leptospirosis between pediatric and adult patients of different age groups

The main objective was to compare the in-hospital case-fatality rate of leptospirosis between pediatric (< 19 years) and adult (>19 years) patients, taking into account gender, renal function, duration of symptoms and jaundice. Medical records of 1016 patients were reviewed. Comparative analysis was restricted to 840 patients (100 pediatric, 740 adults) with recorded information on the variables included in the analysis. Among these patients 81.7% were male and 91.5% were icteric. The case-fatality rate of leptospirosis was 14.4%. The odds of death adjusted for gender, jaundice, duration of symptoms, serum urea and serum creatinine were almost four times higher for the adult than for the pediatric group (odds ratio (OR) = 3.94; 95% confidence interval = 1.19-13.03, p = 0.029). Among adults, increased age was also significantly and independently associated with increased risk of death (p < 0.01). Older patients were also more often treated by dialysis. In conclusion, the data suggest that the in-hospital case fatality rate of leptospirosis is higher for adults than for children and adolescents, even after taking into account the effects of several potential risk factors of death. Among adults, older age was also strongly and independently associated with higher risk of death.     

Postoperative opiate analgesia requirements of smokers and nonsmokers

BACKGROUND: Smoking cigarettes and other forms of nicotine administration appear to blunt the perception of pain. Abrupt discontinuation of nicotine in nicotine-dependent patients appears to increase the perception of pain. The clinical importance of nicotine's effect on pain perception is not fully understood. OBJECTIVE: To determine whether smokers who abruptly discontinue smoking as a result of being hospitalized for coronary artery bypass graft (CABG) require more postoperative opiate analgesics than nonsmokers. METHODS: A retrospective review of patients who underwent a CABG was performed. Smokers (n = 20) were compared with nonsmokers (n = 69) with regard to opiate analgesic use during the first 48 hours postoperatively. The use of nonopiate sedatives was also compared between the groups. RESULTS: When normalized for weight and body mass index, smokers required 23% and 33%, respectively, more opiate analgesics than did nonsmokers (p = 0.027 and 0.023, respectively). The percentage of patients who received benzodiazepines postoperatively was similar in the 2 groups. CONCLUSIONS: In this study, smokers deprived of nicotine required a greater amount of opiates in the first 48 hours after CABG than did nonsmokers. Healthcare providers need to be aware of the potential for increased narcotic requirements among nicotine-deprived smokers. Further study is needed to determine whether nicotine replacement lessens the requirement for postoperative analgesics in smokers.     

Intraductal papillary mucinous neoplasms of the pancreas: an updated experience

OBJECTIVE: To update the authors' experience with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. BACKGROUND DATA: IPMNs are intraductal mucin-producing cystic neoplasms of the pancreas with clear malignant potential. Since the authors' 2001 report, the number of IPMNs resected at our institution has more than doubled, providing an opportunity to define the clinical features of this distinct neoplasm. METHODS: All patients undergoing pancreatic resection for an IPMN at the Johns Hopkins Hospital between January 1987 and March 2003 were evaluated. Noninvasive IPMNs were classified as "adenoma," "borderline," or "carcinoma-in situ" (CIS) depending on the degree of dysplasia within the specimen. Invasive cancers were classified as tubular, colloid, mixed, or anaplastic types. Pathology was retrospectively reviewed to identify main-duct or branch-duct origin of the tumors. Long-term overall survival for patients having IPMNs with invasive cancer was compared with those patients having IPMNs without an invasive component. RESULTS: Between January 1987 and March 2003, inclusive, 136 pancreatic resections were performed for patients with IPMNs, with 78 resections performed since January 2001. The mean age of the patients was 66.8 +/- 1.1 years, with 57% being male and 89% white. Pancreaticoduodenectomy was performed in 71% of patients, total pancreatectomy in 15%, distal pancreatectomy in 12%, and central pancreatic resection in 2%. IPMNs without evidence of invasive cancer were identified in 62% (n = 84) of patients (17% adenoma, 28% borderline, or 55% CIS). The remaining 38% (n = 52) of patients had IPMNs with associated invasive cancer (60% tubular, 27% colloid, 7% mixed, and 6% anaplastic). The mean age of patients with IPMN adenoma was 63.2 years, 66.7 years for those with borderline/CIS IPMNs, and 68.1 years for those with invasive cancer (P = 0.08, adenomas vs. invasive cancer). In those patients with invasive cancers, 15% had invasive cancer at the final surgical margin, 23% had IPMN without invasive cancer at the margin, and 54% had lymph node metastases. Residual IPMN was identified at the neck or uncinate margin in 24% of patients with noninvasive IPMNs. The overall 5-year survival for patients having IPMNs without invasive cancer was 77% (several deaths secondary to metachronous invasive cancer), compared with 43% in those patients with an invasive component (P < 0.0001). There were no differences in survival when comparing adenomas, borderline neoplasms, and CIS. Similarly, there were no statistically significant differences in survival when comparing branch-duct, main-duct, and combined variants; however, the branch-duct variants were more often noninvasive. For those patients with invasive IPMNs, 2-year survival was 40% when margins were positive for invasive cancer or for IPMN without invasive cancer, and 60% when margins were tumor-free (P = 0.15). Those patients with colloid carcinomas (n = 14) had improved survival compared with those with tubular carcinomas (n = 31), with 5-year survival rates of 83% and 24%, respectively. IPMN recurrences and deaths from cancer occurred in patients with both invasive and noninvasive IPMNs at initial resection. CONCLUSIONS: IPMNs continue to be recognized with increasing frequency. Five-year survival for those patients following resection of IPMNs with invasive cancer (43%) is improved compared with those patients with resected pancreatic ductal adenocarcinoma in the absence of IPMN (averages 15%-25%). Survival following resection of IPMNs without invasive cancer (regardless of degree of dyplasia) is good, but recurrent disease in the residual pancreas suggests that long-term surveillance is critical. Based on the age at resection data, there appears to be a 5-year lag time from IPMN adenoma (63.2 years) to invasive cancer (68.1 years).     

Sudden cardiac death: Ethical considerations in the return to play

The team physician-athlete relationship prompts many basic questions in medical ethics. Return-to-play decisions form many of the core responsibilities facing team physicians, and occasionally these decisions can have overriding ethical dilemmas. Therefore, a structured ethical decision-making process is a valuable skill for every successful sports medicine physician. An ethical question is confronted here in a case presentation that weighs the risk of repeat sudden cardiac death and the potential for failed cardiac resuscitation against the athlete’s interest to play competitive basketball. The article applies a four-step framework for ethical decision making in sports medicine. The important first step includes gathering medical information and understanding the preferences of the athlete. Step 2 brings together the decision-making stakeholders, the team physician as a member, to define ethical issues and apply ethical principles: beneficence, nonmaleficence, and patient autonomy. Step 3 selects a course of action with unbiased analysis and arrives at a good choice that merits an action plan in step 4. This decision need not be perfect, but should reinforce the team physician’s responsibilities to the athlete and center on the athlete’s welfare.     

Epidural ropivacaine versus epidural morphine and the catabolic response to colonic surgery: stable isotope kinetic studies in the fasted state and during infusion of glucose

BACKGROUND: The authors examined the hypothesis that epidural administration of local anesthetic, in contrast to epidural analgesia with morphine, inhibits postoperative protein oxidation during administration of glucose. METHODS: Fourteen patients were randomly assigned to undergo a 6-h stable isotope infusion study (3 h fasted, 3 h feeding with 4 mg.kg(-1).min(-1) glucose) on the second day after colorectal surgery using epidural analgesia with either continuous ropivacaine or intermittent morphine. Protein synthesis, breakdown and oxidation, and glucose production were measured by L-[L-13C]leucine and [6,6-2H2]glucose. Substrate oxidation rates were determined by indirect calorimetry. Plasma concentrations of metabolic substrates and hormones were also measured. RESULTS: Whole body protein breakdown, oxidation, synthesis, and glucose production in the fasted state were similar between the two groups. Glucose administration decreased protein breakdown (P = 0.01), protein synthesis (P = 0.001), and glucose production (P = 0.001) to the same extent in both groups, whereas protein oxidation was not significantly affected. The type of epidural analgesia did not significantly influence the circulating concentrations of metabolic substrates and hormones in the fasted or in the fed state. Carbohydrate oxidation rate in the ropivacaine group was greater than in patients receiving morphine (P = 0.04), regardless of whether glucose was infused. CONCLUSION: Epidural analgesia achieved with ropivacaine or morphine does not suppress the catabolic response to surgery, either under fasting conditions or in the presence of an energy supply.     

Video-assisted thoracoscopic surgery of mediastinal bronchogenic cysts in adults: a single-center experience

Background

Mediastinal bronchogenic cysts are rarely diagnosed in adults, hence surgical experience is limited particularly with regard to video-assisted thoracoscopic surgery. In support of the thoracoscopic approach we report our single-center experience in this rare entity.

Methods

Between June 1995 and December 2002, a nonselected series of 12 consecutive patients presenting with mediastinal bronchogenic cysts underwent video-assisted thoracoscopic surgery. Six cysts (50%) had been diagnosed 2 to 22 years prior, only three of which became symptomatic. In asymptomatic patients (n = 7) surgery was performed because of increasing cyst size (n = 3), patient's request (n = 3), or suspected metastasis (n = 1).

Results

Mediastinal bronchogenic cysts were correctly diagnosed by computed tomography in 83% (10/12) and by magnetic resonance imaging in 100% (9/9). Using a three-trocar technique thoracoscopic surgery was successfully performed in 11 of 12 cases (92%). We noted no signs of acute cyst infection. No serious postoperative complications were observed. In 1 patient conversion to open thoracotomy was necessary due to extensive pleural adhesions. In another case thoracoscopic excision of the cyst wall was incomplete. Patients with thoracoscopic excision were discharged after a median of 5.5 days (range 4 to 14 days). No recurrences or complications were observed during a mean follow-up of 40.5 months.

Conclusions

Considering the low conversion and complication rate in our series, video-assisted thoracoscopic surgery should be the primary therapeutic choice among adults with symptomatic mediastinal bronchogenic cysts. Surgical intervention in patients with asymptomatic and uncomplicated cysts appears optional.