Ronald Ross: a century of the transfer of malaria by mosquitoes

Ronald Ross is a brilliant and polyvalent mind. When orientated towards medicine he took the training amateurishly and ended up with a limited qualification. After 2 years as a ship doctor, he attended the compulsory complementary training in order to be admissible in the IMS, the garrison life left him with plenty of time to engage in his hobby's: painting for a short while, writing, poetry and mathematics. By the end of his first term he questioned the sense of his medical activities and decided, with a view to his career, to acquire a Public Health diploma and some complementary bacteriology. During his second term the malaria problem drew his attention. As he was unable to detect the parasite of Laveran in the blood of patients with malarial fevers he concluded that the parasite had been some lucky microscopic finding without any value and turned this parasite into ridicule. During his leave in 1894 he met Manson, who showed him the technique to put the parasite in evidence and convinced him to search for its vector which, to his opinion, should be a mosquito. Ross decided to follow this lead. With his minimal parasitological knowledge and an entomological background limited to the external appearance of mosquitoes he endeavoured to establish the life cycle of the malarial parasites. Notwithstanding some service bounded transfers, he followed the fate of the filaments of the crescents and discovered the parasite on the stomachwall of dapled-winged mosquitoes. During his special mission in Calcutta and in the absence of suitable malaria infections in man he shifted to bird proteosoma (now P. relictum) with a grey mosquito (culex) as vector. He demonstrated the complete life-cycle ending in the salivary glands of the mosquitoes and succeeded in transmitting this infection by mosquito-bites in healthy birds. This climax in his research was crowned by the attribution in 1902 of the Nobel Prize for Medicine. In the mean time he resigned from the IMS and was appointed as "Lecturer on Tropical Diseases" at the Liverpool School. He reoriented his activities to the prevention of malaria by control of the vector in its aquatic larval stage, which he tried out and promoted during his journeys to the West African Coast and other countries. His current were variegated but without salient details. Through the survey of the parasite index and the assessment of the spleen rate in children he founded the malariometry as a epidemiological tool, focussed attention on the relation of malaria and the community and on the complexity of the transmission dynamics. By handing in his resignation at the Liverpool School and moving to London he hampered further his scientific productivity. The tardy foundation of the Ross Institute did not stimulate a new impetus. He suffered a stroke which left him partially crippled an he died in his Institute.     

Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study

PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.     

A prospective study to assess the effect of ambulatory teaching on patient satisfaction

PURPOSE: To assess the effect of ambulatory teaching on patients' satisfaction. METHOD: In 1996, 103 adult patients presenting to the Walter Reed General Medicine Walk-in Clinic completed a patient-satisfaction questionnaire immediately following their visits, during which they were initially seen by a trainee (third-year medical student or intern) and then seen by a faculty preceptor. The questionnaire included five items from the validated Medical Outcomes Study (MOS)-9 questionnaire as well as two open-ended questions. Fourteen staff physicians, 13 students (49% of the visits), and 11 interns (51% of the visits) participated in the study. Satisfaction was analyzed by level of training, and the responses from the study patients were compared with the responses from 372 usual-care (i.e., non-teaching) patients from the same clinic, using the chi-squared test. RESULTS: The study patients were typically pleased with their encounters, rating their overall satisfaction as excellent (61%), very good (29%), or good (9%). Nearly two thirds of the patients rated their satisfaction with waiting time to be very good or excellent. Compared with the usual-care patients, the study patients reported equal or greater satisfaction for all five MOS-9 items. Ninety-five percent of the study patients said they would be willing to be seen by a trainee-staff team on future visits. There was no difference in patient satisfaction by trainee level. The study patients cited enhanced interaction (45%), enhanced education (34%), and improved care (26%) as benefits of trainee-involved care, and increased waiting time (18%) and worse care (5%) as drawbacks. CONCLUSION: The results of this study suggest that ambulatory teaching does not adversely affect patient satisfaction, regardless of trainee level, and that patients who have been seen by trainee-staff teams are willing to experience such encounters again.     

Amiodarone-induced pulmonary toxicity in Fischer rats: release of tumor necrosis factor alpha and transforming growth factor beta by pulmonary alveolar macrophages

Amiodarone is an antiarrhythmic drug with numerous side effects, the most serious being the development of pulmonary toxicity. We have previously reported that a single intratracheal instillation of amiodarone to Fischer 344 rats results in pulmonary fibrosis within 6 wk of treatment. Presently, the mechanism of amiodarone-induced pulmonary toxicity is unknown. Cytokines that stimulate fibroblast proliferation and/or collagen production may play a role in amiodarone-induced pulmonary toxicity. To investigate this possibility, female rats were given a single intratracheal instillation of amiodarone (6.25 mg/kg), its metabolite desethylamiodarone (5 mg/kg), or vehicle (sterile water). At 1, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered cells were counted and identified. The alveolar macrophages were isolated by attachment to plastic petri dishes, cultured overnight, and the spent media collected for tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) analyses. Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-alpha and TGF-beta were not significantly different from control animals. In contrast, amiodarone treatment resulted in a lymphocytic alveolitis and significantly higher amounts of TNF-alpha were observed at 3 and 6 wk after treatment. A trend toward higher levels of TGF-beta was also noted in the amiodarone-treated group at wk 1-3 but the values were not significantly different from those of controls. In conclusion, the release of TNF-alpha may play a role in the development of amiodarone-induced pulmonary toxicity.     

Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes

Protein S deficiency is a known risk factor for thrombosis. The coexistence of phenotypic type I (reduction in total and free antigen) and type III (reduction in free antigen only) protein S deficiencies in 14 of 18 families was recently reported. We investigated the cause of this phenotypic variation in the largest of these families (122 family members, including 44 affected individuals) using both molecular genetic and phenotypic analysis. We have identified a sole causative mutation (Gly295Val) in three family members representative of the variable phenotype. Complete cosegregation of the mutation with reduced free protein S antigen levels was found, regardless of the total antigen level. Analysis of phenotypic data showed high correlations between total protein S antigen and age in both normal and protein S-deficient family members, irrespective of gender. Free protein S antigen levels were not influenced by age, a finding explained by an association between beta-chain containing C4b-binding protein (C4bBP-beta+) antigen levels and age. We propose that the identified Gly295Val mutation causes quantitative, or type I, protein S deficiency, and that as age increases the total protein S antigen level normalizes with respect to the reference plasma pool, giving rise to a type III protein S-deficient phenotype.     

Gonadotrophins and prolactin rise after bilateral oophorectomy for benign conditions

The aim of this study was to analyse the changes in follicle stimulating hormone (FSH), luteinizing hormone (LH) and prolactin concentrations in the 3 months following oophorectomy in pre-menopausal women operated on for benign gynaecological conditions. Included in this analysis were 21 women (mean age 47 years, range 46-52) who underwent bilateral oophorectomy plus hysterectomy for fibroids or ovarian cysts. Plasma concentrations of FSH, LH and prolactin were measured before and on days 2, 4, 6, 14 and 30 after surgery; in 10 cases measurements were made on day 60, and in five cases on day 90 after surgery. Hormone concentrations were measured in duplicate daily samples, and immunoenzymatic assay kits were used for all the immunoassays. The FSH and LH concentrations increased constantly after surgery. Mean prolactin concentrations also increased from 12.1 ng/ml before surgery to 31.5 ng/ml on day 14 after bilateral oophorectomy, but decreased thereafter to 18.2 ng/ml on day 30, 10.9 ng/ml on day 60 and 6 ng/ml on day 90. In conclusion, transient (2-3 weeks) increased prolactin concentrations are observed after surgical castration.     

Mast cell cholangiopathy: another cause of sclerosing cholangitis

A 75-year-old woman with known systemic mastocytosis presented with abdominal pain, ascites, and bile duct thickening on computed tomography and ultrasonography. A liver biopsy specimen showed infiltration with mast cells. Endoscopic retrograde cholangiography showed ductal changes compatible with those found in primary sclerosing cholangitis. Brush cytology of the intrahepatic bile ducts confirmed mast cell infiltration. Systemic mastocytosis can infiltrate the biliary system, producing a cholangiopathy radiographically similar to primary sclerosing cholangitis.