Stem bark alkaloids of Rauwolfia vomitoria

Forty-three indole alkaloids were isolated from 7 kg Rauwolfia vomitoria stem bark; 39 were identified and 2 partially characterised. At least 72 alkaloids classified into 19 types occur in the plant and the interrelationship of the alkaloids and their distribution throughout the plant has been discussed. The major alkaloids of the stems were heteroyohimbines (especially reserpiline) and N (a)-demethyldihydroindoles.     

Loss of sagittal plane correction after removal of spinal implants

STUDY DESIGN: A retrospective review of a clinical series was performed. OBJECTIVES: To evaluate the incidence of adult patients who experienced spinal collapse after spinal implant removal after a long spinal arthrodesis, and to assess the various factors that may influence the likelihood of collapse after implant removal. SUMMARY OF BACKGROUND DATA: Published reports describing the benefits or complications of spinal implant removal do not exist. Spinal implant removal, often considered a benign procedure, is even required by the Food and Drug Administration (FDA) for certain implants. METHODS: The medical records and radiographs of 116 consecutive adult patients with long posterior instrumented fusions (>5 segments) were reviewed. The information obtained included original diagnosis, patient age, number of previous surgeries before implant removal, levels of anterior and posterior fusion, time from fusion to implant removal, time from implant removal to failure, and reason for hardware removal. Radiographs also were assessed including scoliosis, lordosis, and kyphosis measurements before implant removal, after hardware removal, after failure, and after revision surgery. RESULTS: Of 116 patients, 14 underwent spinal implant removal. Most of these patients reported prominent implants either proximally in the thoracic spine or distally in the ilium (Galveston technique). Of these 14 patients, 4 experienced increased pain and collapse after implant removal despite thorough intraoperative explorations demonstrating solid fusion. CONCLUSIONS: Spinal implant removal after long posterior fusion in adults may lead to spinal collapse and further surgery. Removal of instrumentation should be avoided or should involve partial removal of the prominent implant.     

Validation of serotonin (5-hydroxtryptamine) as an in vitro substrate probe for human UDP-glucuronosyltransferase (UGT) 1A6.

Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been limited by a lack of specific substrate probes. In this study serotonin was evaluated for use as a probe substrate for human UGT1A6 using recombinant human UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity at 40 mM serotonin concentration varied more than 40-fold among human livers (n = 54), ranging from 0.77 to 32.9 nmol/min/mg of protein with a median activity of 7.1 nmol/min/mg of protein. Serotonin-UGT activity kinetics of representative human liver microsomes (n = 7) and pooled human kidney, intestinal and lung microsomes and recombinant human UGT1A6 typically followed one enzyme Michaelis-Menten kinetics. Serotonin glucuronidation activity in these human liver microsomes had widely varying V(max) values ranging from 0.62 to 51.3 nmol/min/mg of protein but very similar apparent K(m) values ranging from 5.2 to 8.8 mM. Pooled human kidney, intestine, and lung microsomes had V(max) values (mean +/- standard error of the estimates) of 8.8 +/- 0.4, 0.22 +/- 0.00, and 0.03 +/- 0.00 nmol/min/mg of protein (respectively) and apparent K(m) values of 6.5 +/- 0.9, 12.4 +/- 2.0, and 4.9 +/- 3.3 mM (respectively). In comparison, recombinant UGT1A6 had a V(max) of 4.5 +/- 0.1 nmol/min/mg of protein and an apparent K(m) of 5.0 +/- 0.4 mM. A highly significant correlation was found between immunoreactive UGT1A6 protein content and serotonin-UGT activity measured at 4 mM serotonin concentration in human liver microsomes (R(s) = 0.769; P < 0.001) (n = 52). In conclusion, these results indicate that serotonin is a highly selective in vitro probe substrate for human UGT1A6.     

Squamous cell carcinoma of the penis: Multivariate analysis of prognostic factors and natural history in a monocentric study with a conservative policy

Background: Penile carcinoma is uncommon in Western countries. Here we report on a large series of patients with squamous cell carcinoma (SCC) of the penis, describing prognostic factors, survival and therapeutic results.Patients and methods: From 1973 to 1993, 102 patients with invasive SCC of the penis were treated at the Institut Gustave-Roussy. Precancerous lesions and conditions associated with penis cancer were analyzed retrospectively. Survival curves were estimated by the Kaplan–Meier method, and groups were compared for outcome by the log rank test for univariate comparisons and by Cox's proportional hazards model for multivariate analysis.Results: The median age at onset was 58 years. Sixty-nine patients presented with Jackson's stage I disease, 17 with stage II and 15 with stage III. The interval between the manifestation of symptoms and the diagnosis was more than a year in 13.7% of cases. Precancerous lesions were found in 17 (16.6%) patients, and a history of phimosis was noted in 25 (24.5%). In situ and invasive carcinoma were observed together in 17 (16.6%) cases and dysplasia was associated with invasive carcinoma in eight (7.8%) further cases.Conservative treatment was administered whenever feasible. Interstitial brachytherapy was performed alone or associated with limited surgery (local excision or circumcision) in 72 (70.6%) patients. Of the 28 patients with a local relapse, nine have died of their neoplasms (32%) compared to 21 of 28 patients with lymph node relapse (75%).The median follow-up was 111 months. Disease-free survival, disease-specific survival and overall survival were, respectively, 56%, 72% and 63% at five years and 42%, 66% and 50% at 10 years. Age (P = 0.01), the N status (P < 0.00001) or palpable nodes (P < 0.0038), corpus involvement (P = 0.006) and a verrucous histology (P = 0.038) had significant prognostic relevance for survival in the univariate analysis whereas the performance status, T status and Broders' grade did not. In the multivariate analysis only two parameters, involvement of the corpus (P < 0.0001) and palpable nodes (P = 0.009), were singled out as being independent variables influencing survival. A subgroup of nine patients with verrucous histologies were distinguished by their freedom from node involvement. These patients had an excellent prognosis: all are alive and disease-free. Penile integrity was preserved during follow-up in 54 patients (52.9%), 31 of whom are still alive. Of 72 patients treated by a conservative approach including brachytherapy, long-term penile integrity was maintained in 49 (68%).Conclusion: Corpus involvement and clinically palpable nodes are highly statistically significant independent factors influencing overall survival. Node relapses remain a major cause of death. Thus, better management of lymph nodes is essential for improving survival even when conservative therapy is used to treat the primary.     

Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes.

The predominant metabolic pathway of gemcabene in humans is glucuronidation. The principal human UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of gemcabene were determined in this study. Glucuronidation of gemcabene was catalyzed by recombinant UGT1A3, recombinant UGT2B7, and recombinant UGT2B17, as well as by human liver microsomes (HLM). Gemcabene glucuronidation in recombinant UGTs and HLM followed non-Michaelis-Menten kinetics consistent with homotropic activation, but pharmacokinetics in humans were linear over the dose range tested (total plasma C(max), 0.06-0.88 mM). Gemcabene showed similar affinity (S(50)) for recombinant UGTs (0.92-1.45 mM) and HLM (1.37 mM). S-Flurbiprofen was identified as a more selective inhibitor of recombinant UGT2B7-catalyzed gemcabene glucuronidation (>23-fold lower IC(50)) when compared with recombinant UGT1A3- or recombinant UGT2B17-catalyzed gemcabene glucuronidation. The IC(50) for S-flurbiprofen inhibition of gemcabene glucuronidation was similar in HLM (60.6 microM) compared with recombinant UGT2B7 (27.4 microM), consistent with a major role for UGT2B7 in gemcabene glucuronidation in HLM. In addition, 5,6,7,3',4',5'-hexamethoxyflavone inhibited recombinant UGT1A3 and recombinant UGT2B17-catalyzed gemcabene glucuronidation (with 4-fold greater potency for recombinant UGT1A3) but did not inhibit gemcabene glucuronidation in HLM, suggesting that UGT1A3 and UGT2B17 do not contribute significantly to gemcabene glucuronidation. Reaction rates for gemcabene glucuronidation from a human liver bank correlated well (r(2)=0.722, P<0.0001; n=24) with rates of glucuronidation of the UGT2B7 probe substrate 3'-azido-3'-deoxythymidine. In conclusion, using the three independent experimental approaches typically used for cytochrome P450 reaction phenotyping, UGT2B7 is the major enzyme contributing to gemcabene glucuronidation in human liver microsomes.     

Surgical treatment of metastases from thyroid cancer in the axial skeleton. A retrospective study of 18 cases

Between 1990 and 1997, 18 patients with a mean age of 55.5 years (11 females, 7 males) underwent surgical treatment for a metastasis from thyroid cancer involving the axial skeleton. At the time of surgery all patients had a poor prognosis: 7 metastases revealed the thyroid cancer, all 18 patients had a neurological or mechanical complication, 9 had multiple metastases, all were over 40 years of age. After arteriography with embolization, the surgical procedure consisted of curettage of the tumor and reconstruction, followed by treatment with iodine 131. The survival rate 3 years after surgery was 50%. At the last review, the functional outcome was good and 17 patients had total neurological recovery. Four complications occurred: 1 operative hemorrhage, 3 postoperative infections. Four patients had local recurrence of the metastasis with a one-year survival rate of 20%. When the thyroid cancer was revealed by the axial metastasis, the 3-year-survival rate was 42%. In cases with huge metastases, the 3-year-survival rate was 71%. It appears from these data that surgical treatment of metastases from thyroid cancer in the axial skeleton still achieves a good functional outcome even in cases where neurological or mechanical complications had occurred before surgery.     

The effect of maternal caffeine ingestion on pancreatic function in the neonatal rat

Summary Pancreatic function was investigated in neonatal suckling offspring of caffeine-ingesting dams, with or without maternal sucrose supplementation, throughout pregnancy and lactation. In offspring of rats ingesting caffeine without sucrose supplementation, there was initial hyperinsulinaemia, followed by a progressive fall of plasma insulin to subnormal levels. This fall in plasma insulin coincided with depletion of pancreatic insulin stores. Both the fall in plasma insulin and depletion of pancreatic insulin stores were prevented by sucrose supplementation of caffeine-ingesting dams. Offspring of dams fed sucrose alone and control offspring also maintained pancreatic insulin stores and circulating insulin levels over the first 14 days of postnatal life. Pancreases from offspring of caffeine-exposed animals tested in vitro showed enhanced sensitivity of the insulin release process to glucose. This was reflected in the glucose concentration required to elicit half-maximal insulin release (2.4 ± 0.2 mmol/l for caffeine offspring, 2.3 ± 0.2 mmol/l for caffeine with sucrose, 3.8 ± 0.3 mmol/l for sucrose and 4.1 ± 0.3 mmol/l for control offspring, mean ± SEM). In contrast, offspring of sucrose-supplemented (with or without caffeine) dams showed increased sensitivity of the proinsulin biosynthetic process to glucose, whereas offspring of dams ingesting caffeine alone showed no significant enhancement of the biosynthetic process compared with control offspring. Thus enhanced sensitivity of the insulin secretory process to glucose without a change in the sensitivity of the biosynthetic process in the offspring of the caffeine ingesting (nonsucrose supplemented) dams could explain the progressive depletion of pancreatic insulin stores and eventual hypoinsulinaemia seen in this group.     

Prostatic adenocarcinoma with mandibular metastatic lesion: case report

Metastatic lesions of primary tumors, which originate in different parts of the body, comprise almost 1 % of different types of oral cancers. These lesions can affect either bones or soft tissues in the maxillofacial region. Whenever the maxillofacial area is affected, the most common location is in the molar region of the mandible. The clinical presentation of mandibular metastasis follows a clinical pattern characterized by irradiated dental pain in the third molar region. The most frequent sign is parethesia of the area innervated by the mandibular alveolar dental nerve. Differential diagnosis and treatment of these patients can be extremely difficult because there a number of pathologic conditions with similar symptoms and because diagnostic examination can be highly confusing. The aim of this article is to present a case of prostatic adenocarcinoma where the only metastasis was found in the jaw. A literature review will be presented, hoping to contribute to the scarce information regarding this lesion, due to its low frequency and atypical expression of this type of metastasis in terms of etiology, biological behavior and treatment.