9‐cis retinoic acid is the ALDH1A1 product that stimulates melanogenesis

Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV‐radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV‐induced lipid aldehyde 4‐hydroxy‐2‐nonenal nor the ALDH1A1 product all‐trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9‐cis retinal and its corresponding product 9‐cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA and melanin. ALDH1A1 depletion inhibited the ability of 9‐cis retinal but not 9‐cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalysing the conversion of 9‐cis retinal to 9‐cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9‐cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9‐cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo.     

Neuroanatomical correlates of neurological soft signs in antipsychotic-naive schizophrenia

Recent imaging studies suggest that the so-called “soft” neurological signs in schizophrenia might have neuroanatomical validity. We examined gray matter volume correlates of neurological soft signs (NSS) in antipsychotic-naive schizophrenia patients using an automated image analysis technique. NSS were assessed using a modified neurological evaluation scale with good inter-rater reliability. Magnetic resonance images of 30 schizophrenia patients and 27 age-, sex-, education- and handedness-matched healthy controls were processed using optimized voxel-based morphometry (VBM). Logistic regression analysis showed that only the Motor Sequencing Signs (MSS) sub-score was a significant predictor of subject's status among the NSS sub-scores. Optimized VBM analysis showed that the MSS sub-score had a significant negative correlation with total and regional gray matter volumes (prefrontal, posterior cingulate, temporal cortices, putamen, and cerebellum) in schizophrenia patients but not in controls. Prefrontal and temporal cortices, putamen and cerebellum had significant volume deficits in patients. Cortical and cerebellar correlates of the sub-score MSS support the concept of “cognitive dysmetria” in schizophrenia.     

DNA polymerase III gene of Bacillus subtilis.

The Bacillus subtilis dnaF (polC) gene that codes for the alpha subunit of the DNA polymerase III holoenzyme has been sequenced. It consists of 4005 base pairs coding for 1335 amino acids (from the start to the stop codon), giving a molecular weight of 151,273. A mutation (azp-12) that confers resistance to the antimicrobial drug 6-(p-hydroxyphenylazo)-uracil is due to a single base change at nucleotide 3523, from TCA to GCA, resulting in a change of the 1175th amino acid, serine, to alanine. It is in the active site and located at the C-terminal part of the enzyme. The amino acid composition in an N-terminal domain has 26% homology to the epsilon subunit coded by the dnaQ gene of Escherichia coli, which is a 3'----5' proofreading exonuclease, supporting an earlier observation that this function is an integral part of the polymerase molecule in B. subtilis.     

Radiotherapy for stage I Hodgkin's disease: 20 years experience at St Bartholomew's Hospital

One hundred and one consecutive patients with newly diagnosed stage I Hodgkin's disease (HD) received treatment at St Bartholomew's Hospital, between 1968 and 1987, with a median follow-up of 12 years. Eleven patients have been excluded from detailed analysis because they either received involved field radiotherapy (RT) or radiotherapy with chemotherapy or were lost to follow-up. Actuarial analysis predicts 78% to be alive and without relapse of Hodgkin's disease at 15 years. Ninety evaluable patients (clinical stage (CS) 24; pathological stage (PS) 66) received either mantle or inverted 'Y' RT and form the basis of this analysis. The median age was 33 years (63 men, 27 women). Histology at presentation was nodular sclerosing (39), lymphocytic predominant (27) or mixed cellularity (24). The presenting site was neck (78), axilla (6) groin (4) and mediastinum (2). Complete remission was achieved in all evaluable patients, the actuarial proportion in remission being 75% at 15 years. Factors predictive of a prolonged remission were pathological staging versus clinical staging (P = 0.02) and lymph node size less than 3 cm (P = 0.04). Actuarial overall survival in these 90 patients was 75% at 15 years and none of the above factors correlated with survival. Relapse of HD has occurred in 18 patients (5 within RT field, 10 without and 3 in both). Second remission was achieved in 15/18. The actuarial rate of second remission and survival was 40% at 10 years. Sixteen patients have died, 7 of Hodgkin's disease, 7 of unrelated causes and 2 of second malignancy. A further 3 patients who developed second malignancy are still alive. At 15 years the actuarial mortality related to HD was 12%. These results confirm the importance of long follow up to assess the efficacy of primary therapy.     

EVA treatment for recurrent or unresponsive Hodgkin's disease

Summary Nineteen patients with recurrent or unresponsive Hodgkin's disease who had previously received combination chemotherapy comprising mustine or chlorambucil with vinblastine, prednisolone and procarbazine (MVPP or ChlVPP), were treated with a combination of etoposide, vincristine and adriamycin (EVA). Clinical remission (complete, CR + good partial, GPR) was achieved in eleven of the nineteen patients (58%). The remission rate was similar for patients who had previously responded well to chemotherapy and for those who had previously been poorly responsive. Six patients have relapsed between 3 and 5 months after completion of therapy. The remainder continue in remission, two without further therapy at 7 and 8 months, respectively, and three having had additional radiotherapy while in remission. Myelosuppression was the most important toxicity, but in general this was manageable. These results suggest that EVA may be non-cross-resistant with MVPP and ChlVPP and that it is of potential value in combination chemotherapy for previously untreated patients, even though it is unlikely to be curative when treatment with either MVPP or ChlVPP has failed.     

Endoscopic sinus surgery for orbital subperiosteal abscess secondary to sinusitis.

Subperiosteal orbital abscess (SPA) is a serious complication of paranasal sinusitis, which can lead to blindness or even death. A quick response is necessary as this condition is treatable. Early surgical intervention is indicated if there is risk of visual loss, or if no improvement is observed within 48 hours of starting medical therapy. Three patients with orbital SPA secondary to sinusitis treated successfully by Functional Endoscopic Sinus Surgery (FESS) are presented in this case series. The surgical indications were impending visual loss with an abscess and cellulitis impinging on the optic nerve in one child and in the other two patients, a lack of clinical response within 48 hours after starting systemic antibiotic. CT scans, nasal endoscopy, and ophthalmologic examinations are mandatory during the evaluation process. The advantages of FESS in these patients were the avoidance of external ethmoidectomy and its external facial scar, an early drainage of the affected sinuses, SPA, and the eradication of the disease from the fronto-ethmoidal region leading to an enhanced recovery and a reduced hospital stay. FESS is also a safe, convenient and minimally invasive procedure in patients presenting with serious complications of sinusitis.     

Pharmaceutical intervention for myopia control

Myopia is the result of a mismatch between the optical power and the length of the eye, with the latter being too long. Driving the research in this field is the need to develop myopia treatments that can limit axial elongation. When axial elongation is excessive, as in high myopia, there is an increased risk of visual impairment and blindness due to ensuing pathologies such as retinal detachments. This article covers both clinical studies involving myopic children, and studies involving animal models for myopia. Atropine, a nonselective muscarinic antagonist, has been studied most extensively in both contexts. Because it remains the only drug used in a clinical setting, it is a major focus of the first part of this article, which also covers the many shortcomings of topical ophthalmic atropine. The second part of this article focuses on in vitro and animal-based drug studies, which encompass a range of drug targets including the retina, retinal pigment epithelium and sclera. While the latter studies have contributed to a better understanding of how eye growth is regulated, no new antimyopia drug treatments have reached the clinical setting. Less conservative approaches in research, and in particular, the exploration of new bioengineering approaches for drug delivery, are needed to advance this field.     

A quantitative NMR protocol for the simultaneous analysis of atropine and obidoxime in parenteral injection devices

A rapid selective and accurate quantitative ¹H NMR method was developed for the simultaneous analysis of obidoxime chloride and atropine sulfate, the active components in parenteral injection devices (PID) used for the emergency treatment of poisoning by toxic organophosphates. The spectra were acquired in 90% H₂O–10% D₂O using sodium 3-(trimethylsilyl)-1-propane sulfonate hydrate as the internal standard. Both synthetic mixtures and dosage forms were assayed. The results were compared with those obtained from a reported HPLC method.