In search of the biopsychosocial perspective: an experiment with beginning medical students

The authors assessed the clinical thinking of medical students before, during, and after their first extensive in-hospital learning experience and exposure to physician role models. They found that more than 90% of the students' requests for additional data in response to videotaped simulated patient interviews were for biologic information; approximately 66% of all respondents in six separate trials failed to request a single psychological or social item concerning the patient. The authors discuss the pervasiveness of the biomedical rather than the biopsychosocial mentality and its implications for medical education as well as clinical teaching, decision making, and practice.     

PLASMID MEDIATED DRUG RESISTANCE IN VIBRIO CHOLERAE 0139 BENGAL

Sixteen strains of Vibrio cholerae were isolated from cases of diarrhoea. Out of these, 12 (75%) were identified as Vibrio cholerae 0139 synonym Bengal and 4 (25%) as Vibrio cholerae El Tor by standard biochemical and serological tests. Modified CAMP reaction in sheep blood agar showed that 0139 produced moderate hemolysis, El Tor produced wider zone of hemolysis whereas Classical Vibrio cholerae produced no zone of hemolysis (CAMP negative). Break point minimum inhibitory concentration (MIC) by agar dilution method showed that all 0139 strains were resistant to ampicillin 8 mg/L, streptomycin 1 mg/L, chloramphenicol 8 mg/L, sulphamethoxazole 32 mg/L and trimethoprim 0.3-128 mg/L, 58.3% were sensitive to gentamicin 1 mg/L, and all were sensitive to norfloxacin 1 mg/L and cefotaxime 1 mg/L. Resistance to trimethoprim, sulphamethoxazole, ampicillin and gentamicin in 5 strains could be transferred to E coli K-12 by conjugation experiment at a rate of 5×10⁻⁶ to 4×10⁻³. Distinct plasmid bands of 35.8 mega daltons could be seen in agarose gel electrophoresis.KEY WORDS: CAMP test, Drug resistance, Plasmid, Vibrio cholerae 0139.     

RalA is overactivated in medulloblastoma

Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl–geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.     

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady‐state exposures (area under the concentration curve from 0 to 12‐h [AUC_0–>12 h]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m²/dose) or a pharmacokinetically guided dose targeting an AUC_0–>12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in‐target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sorafenib pharmacokinetics (PKs) show large interindividual variability given fixed doses (90 mg/m²/dose twice daily). This leads to a wide exposure range, particularly higher exposures, which can lead to hand foot skin reaction (HFSR), withheld doses, and therefore a possible lower antitumor efficacy.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can PK and pharmacodynamic modeling and simulation approaches provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides evidence, through PK and pharmacodynamic simulations, that it is possible to decrease the variability of sorafenib exposure, increase the percentages of studies in a target range, and reduce the occurrence of HFSR.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials, including our prospective protocol in children with rare solid malignancies.     

UREAPLASMAS UREALYTICUM AND HUMAN INFERTILITY: EFFECT ON SPERMATOZOA MORPHOLOGY

Seminal fluids of 197 males with complaints of involuntary infertility were examined for spermatozoal counts, morphological changes in the spermatozoa and cultured for ureaplasmas and mycoplasmas. In 12, no spermatozoa were present, 29 had a count of less than one million and 156 had more than one million spermatozoa per mL of the seminal fluid. Various morphological changes were detected in the spermatozoa in some cases. U urealyticum and M hominis were grown in 43.15% and 16.75% in comparison to control figures of 15.9% and 11.4% respectively. There was no correlation between growth of ureaplasmas and the spermatozoal count. Among the morphological changes, presence of coiled tails, presence of a fuzzy coat around the tail and microcolonies were highly specific for culture positivity (98.2, 98.2 and 97.35% respectively) but of low sensitivity (55.2%, 14.1% and 8.2% respectively).KEY WORDS: Mycoplasma, Spermatozoa, Ureaplasma