Practical guidelines for screening and treatment of retinopathy of prematurity in Saudi Arabia

Retinopathy of Prematurity (ROP) is one of the leading causes of bilateral blindness in childhood. Early detection and effective treatment can prevent blindness. Efficient and timely screening examination of the retina by an experienced ophthalmologist who deals with preterm neonates with ROP is the mainstay in the management of this disease. All neonatologists and pediatricians who care for these at-risk preterm neonates should also be aware of this timing. This practical guideline intends to provide guidance to ophthalmologists, neonatologists and allied health care professionals in Saudi Arabia on current indications for screening and management of retinopathy of prematurity to prevent or minimize subsequent complications. This practical guideline was led by the National Eye Health Program (NEHP) and Neonatology Services Improvement Program at Ministry of Health (MOH), furthermore it has been solicited and endorsed from both Saudi Ophthalmological Society (SOS) and Saudi Neonatology Society (SNS).     

Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma

BACKGROUND AND PURPOSE: In this study on PDR treatment planning of utero-vaginal carcinoma, we analysed the dosimetry of traditional X-ray based plans as it presents on MR images. The potential gain of MRI-based dose optimisation was assessed. PATIENTS AND METHODS: Sixteen patients boosted with PDR brachytherapy after external beam therapy were included. The clinical X-ray based plans were projected on MR images. The GTV, HR-CTV and IR-CTV were retrospectively contoured, as well as the bladder, rectum and sigmoid colon. The dose in the critical organs and target coverage was investigated. In a second phase, the plans were manually optimised using the MR information. The objectives were to lower the dose in the critical organs (85Gy(alphabeta3) for bladder, 75Gy(alphabeta3) for rectum and sigmoid colon) and to increase the HR-CTV dose to D9085Gy(alphabeta10). RESULTS: In the X-ray based plans, D(2cc) in bladder and sigmoid colon exceeded the tolerance doses in 10/16 and 7/16 patients, respectively. Coverage of the IR-CTV with the 60Gy(alphabeta10) was acceptable. D90 of the HR-CTV was below 85Gy(alphabeta10) in 13 out of 16 patients. After optimisation, the dose constraints in the OAR were not exceeded anymore in any patient. The average D(2cc) dose reduction was 7+/-6Gy(alphabeta3) in the bladder and 7+/-4Gy(alphabeta3) in the sigmoid colon for those patients in which the dose constraint was initially exceeded. In addition, an average dose increase of 3Gy(alphabeta10) was accomplished in the HR-CTV. CONCLUSIONS: MRI-based dose optimisation can play an important role to reduce the dose delivered to the critical organs and to improve target coverage.     

Isoxazolines as potent antagonists of the integrin alpha(v)beta(3)

Starting with lead compound 2, we sought to increase the selectivity for alpha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha to the carboxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It was found that guanidine mimetics with a wide range of pK(a)'s were potent antagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)beta(3)-mediated adhesion versus alpha(IIb)beta(3)-mediated platelet aggregation, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the alpha-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides were optimal. In addition, the selective alpha(v)beta(3) antagonist 3h was found to be a potent inhibitor of alpha(v)beta(3)-mediated cell migration.     

Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons

Opioids mediate their analgesic effects by activating mu-opioid receptors (MOR) not only within the central nervous system but also on peripheral sensory neurons. The peripheral analgesic effects of opioids are best described under inflammatory conditions (e.g., arthritis). The present study investigated the effects of inflammation on MOR binding and G-protein coupling of full versus partial MOR agonists in dorsal root ganglia (DRG) of primary afferent neurons. Our results show that Freund's complete adjuvant (FCA) unilateral hindpaw inflammation induces a significant up-regulation of MOR binding sites (25 to 47 fmol/mg of protein) on DRG membranes without affecting the affinity of either full or partial MOR agonists. In our immunohistochemical studies, the number of MOR-immunoreactive neurons consistently increased. This increase was mostly caused by small-diameter nociceptive DRG neurons. The full agonist DAMGO induced MOR G-protein coupling in DRG of animals without FCA inflammation (EC50 = 56 nM; relative Emax = 100%). FCA inflammation resulted in significant increases in DAMGO-induced MOR G-protein coupling (EC50 = 29 nM; relative Emax = 145%). The partial agonist buprenorphine hydrochloride (BUP) showed no detectable G-protein coupling in DRG of animals without FCA inflammation; however, partial agonist activity of BUP-induced MOR G-protein coupling was detectable in animals with FCA inflammation (EC50 = 1.6 nM; relative Emax = 82%). In behavioral studies, administration of BUP produced significant antinociception only in inflamed but not in noninflamed paws. These findings show that inflammation causes changes in MOR binding and G-protein coupling in primary afferent neurons. They further underscore the important differences in clinical studies testing peripherally active opioids in inflammatory painful conditions.     

Imipramine-induced antinociception in the formalin test. Receptor mechanisms involved and effect of swim stress

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10-40 mg/kg) and 0.5-3 min of swim stress (17 degrees C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through alpha(2)-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.     

Synthesis and Antidepressant Evaluation of Five Novel Heterocyclic Tryptophan‐Hybrid Derivatives

This study aimed at evaluating the reactivity of L ‐Tryptophan (TRP) 1 towards various chemical reagents to produce new bi‐ and tri‐heterocyclic systems providing basic pharmacological activities. Indol‐3‐yl hydroxyoxazol‐2‐yl acetonitrile derivatives 5 and 6 , indol‐3‐yl‐hydroxyoxazol‐2‐yl‐1,2,4‐triazine derivatives 8 and 9, indol‐3‐yl‐hydroxyoxazol‐2‐yl‐aminopyrazole derivatives 11a, b, and indol‐3‐yl‐hydroxyoxazol‐2‐yl‐aminoisoxazole derivative 12 were synthesized via straightforward and efficient methods. The structures were characterized by spectral data (IR, ¹H‐NMR, ¹³C‐NMR, and MS) and the purity was ascertained by microanalysis. Also, this work was extended to study the potential role of the novel synthesized TRP derivatives 5 , 6 , 9 , 11a , and 12 as antidepressant and sedative agents in comparison with TRP. All compounds showed significant antidepressant activity in the forced‐swimming test at two doses (50 or 100 mg/kg). Also, all tested compounds (at 50 or 100 mg/kg) produced a significant decrease in locomotor activity of mice during a 30 min observation period. The most potent antidepressant and sedative effect was produced by the tri‐heterocyclic compounds 9 and 12 , followed by 11a and TRP.     

p53 mutation in HCV-genotype-4 associated hepatocellular carcinoma in Egyptian patients

HCV-associated hepatocellular carcinoma (HCC) is a common neoplasm in Egypt where genotype-4 is prevalent. In the present study the incidence and pattern of p53 mutations was assessed in relation to HCV-genotype- 4 in Egyptian HCC patients. We investigated 25 HCV positive HCCs for p53 mutations/overexpression in relation to HCV-NS3 by immunohistochemistry, SSCP and sequencing. Genotyping was done using LiPA-II and TRUGENE 5' NC' sequencing kit. Results were correlated to standard clinicopathologic prognostic factors for HCC. Thirteen cases showed p53 overexpression, and 10 showed p53 mutation (13 mutations) by sequencing (72% concordance). The highest mutation rate was in exons 6 and 7 (30%) followed by exons 5 and 8 (20%). Mutations included 3 transitions, 5 transversions, 3 deletions, and 2 insertions. All exon 7 mutations were at codon 249 specific for AFB1 (AGG-->AGT, Arg-->Ser) and codon 248 specific for vinyl chloride contamination (CGG-->TGG, Arg-->Trp). Other mutations reported are novel. Immunostaining for HCV NS3 was detected in 19 cases independent of p53 mutation. p53 aberrations were significantly associated with poor prognostic factors for HCC. However, no specific pattern for p53 mutations was observed in HCV genotype 4-associated HCC and no significant relation between p53 mutations, HCV-NS3 expressions or any HCV sub-genotype-4 sequence.     

Natural Products for Chemopreventive and Adjunctive Therapy in Oncologic Disease

Nutritional supplements or complementary and alternative medicines (CAM) are currently being investigated for their use in preventing, inhibiting, and reversing the progression of cancer. Natural agents and their derivatives such as vitamin A, selenium, green tea, resveratrol, aspirin, and probiotics have potential benefits in chemoprevention. There is also growing evidence for the use of natural products as adjunctive therapy alongside conventional cancer treatments. Nutritional supplements expenditures demonstrated greater growth than pharmaceuticals, with approximately 80% of cancer patients using natural products. Current issues with nutritional supplements use in cancer treatment include insufficient or conflicting evidence, poor quality control, potential interactions with chemotherapy, and potential efficacy in relation to changes in certain biomarkers, but long-term implications remain largely unresolved. Continued research is needed to lend credibility to these potentially valuable naturally driven supplements in the prevention and potentially in the treatment of cancer in conjunction with standard pharmaceuticals.     

Nutritive value of traditional sweets consumed in the Arab Gulf countries

Proximate, mineral, fatty acid and cholesterol composition of eight traditional sweets commonly consumed in the Arab Gulf countries were determined. Four sweets were obtained from Bahrain, whereas the other sweets were obtained from Oman. Protein level ranged from 0.2 to 9.0%, while the fat content ranged from 7.9 to 18.0%. In general, the sweets were found to be high in energy content but poor in most minerals. Iron and zinc contents were low (less than 2 and less than 1 mg/100 g for iron and zinc, respectively). Cholesterol was high in four sweets (range from 10.6 to 20.4 mg/100 g), mainly because of the use of animal fat in preparation of these sweets. The fatty acids profiles showed that palmitic and oleic acids were predominant. One sweet (eggbaith) was found to be very high in linoleic (42%) and low in palmitic (9.6%) acids. The study showed that some traditional sweets are nutritious, while others should be consumed with moderation.     

High Density Lipoprotein (HDL) Modulation Targets

Given the strong genetic determinants of favorable HDL-C levels, the ability to procure the cardiovascular disease and longevity benefits associated with this mediator of the reverse cholesterol transport pathway through pharmaceutical intervention is challenging. Niacin is still the most robust HDL-C raising pharmaceutical agent on the market at its use leads to elevations up to 35%. Cholesteryl ester transfer protein (CETP) and endothelial lipase (EL) are two targets involved in the reverse cholesterol transport pathway that have become therapeutic targets of various investigations for raising HDL. However, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was stopped in December 2006 due to excess mortality in the group of patients treated with torcetrapib, a CETP inhibitor. Other CETP inhibitors being studied include anacetrapib and JTT-705. Other CEPT inhibitors including TA-8995, DRL-17822, JTT-302, and others are under investigation. Additionally a biologic target CETi-1, an investigational vaccine in phase II development designed to elicit antibodies that bind and inhibit the activity of CETP leading to blocking the ability of the protein to transfer cholesterol from HDL to LDL and thus causing HDL cholesterol levels to rise is under clinical investigation for sometime.