Retinitis pigmentosa associated with rhodopsin mutations: Correlation between phenotypic variability and molecular effects

Similar retinitis pigmentosa (RP) phenotypes can result from mutations affecting different rhodopsin regions, and distinct amino acid substitutions can cause different RP severity and progression rates. Specifically, both the R135L and R135W mutations (cytoplasmic end of H3) result in diffuse, severe disease (class A), but R135W causes more severe and more rapidly progressive RP than R135L. The P180A and G188R mutations (second intradiscal loop) exhibit a mild phenotype with regional variability (class B1) and diffuse disease of moderate severity (class B2), respectively. Computational and in vitro studies of these mutants provide molecular insights into this phenotypic variability.     

Delayed cytotoxic effects of methyl jasmonate and cis-jasmone induced apoptosis in prostate cancer cells

Advanced prostate cancer cells are typically hormone independent, resistant to apoptosis and do not respond to chemotherapeutic agents. The ability of methyl jasmonate (MJ) and cis-jasmone (CJ) to inhibit growth in hormone independent prostate cancer cell lines, PC-3 and DU-145, was evaluated. CJ and MJ inhibited cell growth, induced cell cycle arrest and apoptosis. Detailed studies with the PC-3 cell line revealed that 2 mM CJ or MJ treatment resulted in caspase 3 activation and Tumor Necrosis Factor Receptor 1 (TNFR1) activation, all hallmarks of apoptosis. These phytochemicals could be useful in the management of advanced prostate cancer.     

CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

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A prospective crossover pilot study to evaluate the use of a topical wound gel in patients with cutaneous toxicity caused by epidermal growth factor receptor inhibitors

One of the dose-limiting toxicities of epidermal growth factor receptor inhibitors (EGFRIs) is a papulopustular rash that is often pruritic and painful. Secondary skin infection can occur from scratching to relieve the pruritus. Studies suggest that this rash might be a surrogate marker for efficacy; therefore, effective rash management is needed to allow patients to use EGFRIs without unnecessary dose modifications. In this single-center, prospective, crossover study, we evaluated the use of a topical gel (Regenecare Wound Gel) for relieving the pruritus and pain of EGFRI-induced rash among oncology patients. The secondary end points were patient satisfaction, adverse effects, and EGFRI dose modifications. At the occurrence of grade 2 skin rash, patients started applying the study gel to the right side of their face; after 1 week, they began applying it to both sides of their face for up to an additional 5 weeks. Each week, providers performed a facial evaluation and patients rated their symptoms and satisfaction on questionnaires. Of the 20 patients enrolled, 13 were evaluable. Reduction in itch at the end of week 1 was greater on the right (treated) side in 69% of patients greater on the left (untreated) side in 8%, and the same in 23% (P = 0.01). The pattern was similar for pain, but the differences were not significant. On average, patients rated the gel as being moderately to extremely effective for alleviating symptoms, improving rash appearance, and promoting healing and found it easy to apply. No adverse effects were documented. Four patients (31%) required EGFRI dose modifications because of rash. Taken together, these findings suggest that the topical wound gel is effective in relieving rash-associated itching in patients receiving EGFRIs and is associated with high patient satisfaction.     

Potentiation of analgesic efficacy but not side effects: co-administration of an α4β2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats

Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4β2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 μmol/kg, i.p.) induced a 6-fold leftward shift of the dose–response of ABT-594 (ED₅₀ = 26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED₅₀ = 26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED₅₀ = 1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose–response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 μmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4β2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4β2 nAChR by PAM may represent a novel analgesic approach.     

Assessment of biological activity of novel peptide analogues of angiotensin IV

Objectives Angiotensin IV (Ang IV) is a metabolite of angiotensin II which acts on specific AT₄ receptors identified as the enzyme insulin regulated aminopeptidase (IRAP). The transduction process of these receptors is unresolved, but Ang IV inhibits the aminopeptidase activity. Ang IV improves cognition in animal models thus there is a desire to develop metabolically stable analogues for further development. Methods Peptide analogues of Ang IV were obtained commercially or synthesised. Each peptide was tested in vitro for its ability to inhibit the aminopeptidase activity (IRAP) of mouse brain homogenates and for its effects on isolated rat uterine smooth muscle. Key findings [Des‐Val¹]‐Ang IV, acetylated‐Ang IV‐amide, Ang IV‐amide and [des‐His⁴]‐Ang IV all inhibited IRAP. [Sar¹, Ile⁸]‐Angiotensin II (10 µm ) had an effect greater than that of Ang IV or any of the other analogues studied. In isolated uterine smooth muscle, angiotensins II and IV induced contractions, which could be antagonised by an AT₁‐receptor antagonist. None of the novel peptides induced uterine smooth muscle contractions, but [Sar¹, des Arg²‐Gly⁸]‐angiotensin II showed significant antagonism of the contractile effects of angiotensin II and carboxyamide‐terminated Ang IV‐NH₂ showed antagonism of Ang IV‐induced contractions. Conclusions This study provides five novel inhibitors of IRAP worthy of assessment in behavioural models of learning and memory. The analogues are devoid of AT₁ receptor agonist properties, and the carboxyamide analogue presents an opportunity to elucidate the mechanism of action of Ang IV as, like Ang IV, it inhibits IRAP, but antagonises the effects of Ang IV on isolated smooth muscle.     

Role of Clinical Images Based Teaching as a Supplement to Conventional Clinical Teaching in Dermatology

Introduction:

Clinical Dermatology is a visually oriented specialty, where visually oriented teaching is more important than it is in any other specialty. It is essential that students must have repeated exposure to common dermatological disorders in the limited hours of Dermatology clinical teaching.

Aim:

This study was conducted to assess the effect of clinical images based teaching as a supplement to the patient based clinical teaching in Dermatology, among final year MBBS students.

Methods:

A clinical batch comprising of 19 students was chosen for the study. Apart from the routine clinical teaching sessions, clinical images based teaching was conducted. This teaching method was evaluated using a retrospective pre-post questionnaire. Students’ performance was assessed using Photo Quiz and an Objective Structured Clinical Examination (OSCE). Feedback about the addition of images based class was collected from students.

Results:

A significant improvement was observed in the self-assessment scores following images based teaching. Mean OSCE score was 6.26/10, and that of Photo Quiz was 13.6/20.

Conclusion:

This Images based Dermatology teaching has proven to be an excellent supplement to routine clinical cases based teaching.