Paravertebral paraganglioma with spinal extension: a case report.

BACKGROUND: Paragangliomas are rare neuroendocrine tumors. While paragangliomas of the spine are rare, those located in non-cauda equina areas with spinal canal extension are even rarer. CASE PRESENTATION: We present a case of a 23-year-old female of African descent with a primary thoracic paraganglioma with intervertebral extension resulting in displacement and compression of the spinal cord and extensive local invasion of the surrounding structures. This paraganglioma was functional with typical symptoms of catecholamine excess. Despite the aggressive nature of the paraganglioma, the patient only had isolated sensory symptoms in the left shoulder. Adequate alpha and beta-blockade were instituted prior to her undergoing surgery with near-total resection and complete preserved neurology. There was no underlying pathogenic genetic mutation found. CONCLUSIONS: Even though rare, paraganglioma should be considered in the differential diagnosis of spinal tumors. Genetic testing should be performed in patients with paragangliomas. One should exercise extreme caution in treating such rare tumors that may cause neurological deficits and careful surgical planning should be undertaken to avoid possible catastrophic complications.

DFT and In-silico Investigations, along with In-vitro Antitumor and Antimicrobial Assessments of Pharmacological Molecules.

BACKGROUND: Molecules bearing an active methylene bridge are one of the most fruitful and remarkable precursors that have been incorporated into the synthetic strategy of an assortment of bioactive compounds. OBJECTIVE: The reactive methylene derivatives have been endowed with multiple reactions, which target biological and medicinal applications and result from their structural diversity and discrete reactivity. METHODS: The present report endeavors to synthesize, characterize, and in-vitro evaluate several novel propanoic acids, coumarin, and pyrazole derivatives as antimicrobial and antiproliferative agents. The in-silico molecular docking, physicochemical, pharmacokinetic/ADMET, bioactivity, and drug-likeness predictions were conducted for all the synthesized compounds. RESULTS: The highest docking score is -9.9 and -8.3 kcal/mol, respectively, for compound 9 (azocoumarin) and 13 (acrylic acid derivative) with the target proteins E. coli topoisomerase II, DNA gyrase subunit B and PI3K p110α domain, respectively. Moreover, this study predicts the synthesized molecules that may inhibit the novel COVID-19, obtained through virtual screenings only, where compounds 9, 13, 14, 17, and 19 came to the limelight with good docking scores i.e., more than -8 Kcal/mol. Safety profiling of the most potent compound 9 was utilized against normal cell lines and the hemolytic effect on RBCs. CONCLUSION: The in-silico ADMET studies of the synthesized compounds revealed moderate to good -likeness, high gastro intestinal (GI) absorption, and inhibiting the Cytochrome CYP2C19 and CYP2C9 and all the derivatives possess non-cancerous nature. The in-vitro screening demonstrated that several of the novel molecules are promising drug candidates. The density functional theory (DFT) theoretical calculations were performed to calculate the energy levels of the FMOs and their energy gaps, dipolemoment, andmolecular electrostatic potential. Such parameters, along with the physicochemical parameters, could be a good tool to confirm biological activity.

Involvement of EZH2, SUV39H1, G9a and associated molecules in pathogenesis of urethane induced mouse lung tumors: potential targets for cancer control.

In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control.

Estradiol treatment prevents injury induced enhancement in spinal cord dynorphin expression.

Administration of the ovarian steroid estradiol in male and female animals has been shown to have neuromodulatory and neuroprotective effects in a variety of experimental models. In the present study, spinal tissues from dermatomes just above (T5-T7, at level) a severe chronic spinal cord injury (SCI) at T8 were analyzed for expression levels of prodynorphin (PRDN) and phospho-(serine 369) κ-opioid receptor (KOR-P) in 17 ß estradiol (EB)- and placebo-treated adult male rats. Dynorphin was targeted since (1) it has previously been shown to be elevated post-SCI, (2) intrathecal injection of dynorphin produces several of the same adverse effects seen with a SCI, and (3) its increased expression is known to occur in a variety of different experimental models of central neuropathic pain. A significant elevation of extracellular levels of both PRDN and KOR-P in the placebo-treated SCI group relative to uninjured surgical sham controls was found in spinal tissues above the injury level, indicating increased dynorphin levels. Importantly, the EB-treated SCI group did not show elevations of PRDN levels at 6 weeks post-injury. Immunohistochemical analysis of at level tissues revealed that EB treatment significantly prevented a post-SCI increase in expression of PRDN puncta co-labeling synapsin I, a nerve terminal marker. The dynorphin-containing terminals co-labeled vesicular glutamate receptor-2 (a marker of glutamatergic terminals), a finding consistent with a non-opioid basis for the adverse effects of dynorphin. These results support a beneficial role for EB treatment post-SCI through a reduction in excessive spinal cord levels of dynorphin. Studies manipulating the timing of the EB treatment post-injury along with specific functional assessments will address whether the beneficial effects are due to EB's potential neuromodulatory or neuroprotective action.

Genotoxic effects of tobacco chewing.

Tobacco chewing is a widespread habit which leads to DNA damage. We are reporting a case of a tobacco chewer in which chromosomal aberrations, DNA breakage, buccal micronuclei and urinary thioether excretion level were studied. The study was carried out on a 28 year old male subject who is polio affected since his childhood. He has been chewing tobacco since the last 17 yrs @ 4 g, 08 times per day. The medical report of the subject indicates no abnormalities except post-polio paralysis in both lower limbs. He has no family history of any genetic disorder. He is not occupationally exposed to tobacco. The findings of the present investigation indicate increased incidence of chromosomal aberration % and micronuclei in buccal epithelial cells than the control values obtained from a subject of similar age and socioeconomic condition but not addicted to tobacco chewing. However, the urinary thioether values of the subject were lower than control values indicating a depression of the detoxification pathway.

No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent.

OBJECTIVE: We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. METHODS: Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using TaqMan polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene-gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). RESULTS: Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. CONCLUSION: Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding.

Sex and hormonal variations in the development of at-level allodynia in a rat chronic spinal cord injury model.

The development of central neuropathic pain varies among patients with spinal cord injury (SCI). The factors contributing to the development and perpetuation of segmental pain (at-level allodynia) has been the focus of ongoing experiments in our laboratory. One such factor is hormonal status. We have shown previously, using a male rat model of SCI, that a severe contusion injury is necessary for the development of allodynia in trunk regions at and just above the level of a T8 injury. In this study, we examined at-level sensitivity for SCI ovariectomized (ovx) and cycling female rats as well as for SCI males implanted with either a placebo pellet or one that slowly releases 17beta-estradiol. The proportion of ovx SCI female rats and placebo-treated SCI males displaying pain-like behaviors to touch/pressure of at-level dermatomes up to 6 weeks post-injury (67% and 75%, respectively) was similar to our previous studies on SCI males (69%). In contrast, significantly fewer cycling SCI female rats and 17beta-estradiol treated SCI male rats showed sensitivity to touch at-level (26% and 30%, respectively). These results implicate 17beta-estradiol as a potential target that can readily be modulated to prevent segmental pain following SCI.

Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of nuclear factor-kappaB-inducing kinase and p38 mitogen-activated protein kinase: a potential role of MMP-9 in myopathy.

Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting. However, the underlying mechanisms leading to extracellular matrix breakdown in skeletal muscle tissues remain unknown. Using a microarray approach, we investigated the effect of tumor necrosis factor-related weak inducer of apoptosis (TWEAK), a recently identified muscle-wasting cytokine, on the expression of extracellular proteases in skeletal muscle. Among several other matrix metalloproteinases (MMPs), we found that the expression of MMP-9, a type IV collagenase, was drastically increased in myotubes in response to TWEAK. The level of MMP-9 was also higher in myofibers of TWEAK transgenic mice. TWEAK increased the activation of both classical and alternative nuclear factor-kappaB (NF-kappaB) signaling pathways. Inhibition of NF-kappaB activity blocked the TWEAK-induced production of MMP-9 in myotubes. TWEAK also increased the activation of AP-1, and its inhibition attenuated the TWEAK-induced MMP-9 production. Overexpression of a kinase-dead mutant of NF-kappaB-inducing kinase or IkappaB kinase-beta but not IkappaB kinase-alpha significantly inhibited the TWEAK-induced activation of MMP-9 promoter. The activation of MMP-9 also involved upstream recruitment of TRAF2 and cIAP2 proteins. TWEAK increased the activity of ERK1/2, JNK1, and p38 MAPK. However, the inhibition of only p38 MAPK blocked the TWEAK-induced expression of MMP-9 in myotubes. Furthermore the loss of body and skeletal muscle weights, inflammation, fiber necrosis, and degradation of basement membrane around muscle fibers were significantly attenuated in Mmp9 knock-out mice on chronic administration of TWEAK protein. The study unveils a novel mechanism of skeletal muscle tissue destruction in pathological conditions.

Relationship of spinal dynorphin neurons to delta-opioid receptors and estrogen receptor alpha: anatomical basis for ovarian sex steroid opioid antinociception.

Pharmacological and behavioral studies suggest that spinal delta- and kappa-opioid antinociceptive systems are functionally associated with ovarian sex steroids. These interactions can be demonstrated specifically during pregnancy or hormone-simulated pregnancy (HSP). The analgesia associated with both conditions can be abolished by blockade of either spinal kappa-opioid receptors or delta-opioid receptors (DOR). Furthermore, both dynorphin (DYN) release (J Pharmacol Exp Ther 298:1213-1220, 2001) and the processing of the DYN precursor (J Neurochem 65:1374-1380, 1995) are significantly increased in the spinal cord during HSP. We undertook the current study to determine whether DYN, DOR, and estrogen receptor alpha (ERalpha) share anatomical relationships that permit their direct interaction. Coexpression of DOR or ERalpha by DYN neurons was assessed using fluorescence immunohistochemistry and a synaptosomal release assay. Findings show that ERalpha and DYN are coexpressed. Moreover, in the spinal cord of HSP animals, there were significant increases in the number of DYN-immunoreactive (DYN-ir) cells, ERalpha-ir cells, cells double-labeled for DYN-ir and ERalpha-ir and the proportion of DYN-ir cells coexpressing ERalpha. Some varicose fibers in the spinal cord dorsal horn and intermediate gray matter that expressed DYN-ir also expressed DOR-ir. Activation of DORs located on DYN terminals was sufficient to inhibit K(+)-evoked DYN release. These data define, at least in part, the anatomical substrates that may be relevant to the antinociception of gestation and its hormonal simulation. Furthermore, they provide a framework for understanding sex-based nociception and antinociception and suggest novel strategies for treating pain.

Ruthenium(II) polypyridyl complexes: potential precursors, metalloligands, and topo II inhibitors.

Neutral and cationic mononuclear complexes containing both group 15 and polypyridyl ligands [Ru(kappa3-tptz)(PPh3)Cl2] [1; tptz=2,4,6-tris(2-pyridyl)-1,3,5-triazine], [Ru(kappa3-tptz)(kappa2-dppm)Cl]BF4 [2; dppm=bis(diphenylphosphino)methane], [Ru(kappa3-tptz)(PPh3)(pa)]Cl (3; pa=phenylalanine), [Ru(kappa3-tptz)(PPh3)(dtc)]Cl (4; dtc=diethyldithiocarbamate), [Ru(kappa3-tptz)(PPh3)(SCN)2] (5) and [Ru(kappa3-tptz)(PPh3)(N3)2] (6) have been synthesized. Complex 1 has been used as a metalloligand in the synthesis of homo- and heterodinuclear complexes [Cl2(PPh3)Ru(micro-tptz)Ru(eta6-C6H6)Cl]BF4 (7), [Cl2(PPh3)Ru(mu-tptz)Ru(eta6-C10H14)Cl]PF6 (8), and [Cl2(PPh3)Ru(micro-tptz)Rh(eta5-C5Me5)Cl]BF4 (9). Complexes 7-9 present examples of homo- and heterodinuclear complexes in which a typical organometallic moiety [(eta6-C6H6)RuCl]+, [(eta6-C10H14)RuCl]+, or [(eta5-C5Me5)RhCl]+ is bonded to a ruthenium(II) polypyridine moiety. The complexes have been fully characterized by elemental analyses, fast-atom-bombardment mass spectroscopy, NMR (1H and 31P), and electronic spectral studies. Molecular structures of 1-3, 8, and 9 have been determined by single-crystal X-ray diffraction analyses. Complex 1 functions as a good precursor in the synthesis of other ruthenium(II) complexes and as a metalloligand. All of the complexes under study exhibit inhibitory effects on the Topoisomerase II-DNA activity of filarial parasite Setaria cervi and beta-hematin/hemozoin formation in the presence of Plasmodium yoelii lysate.

WITHDRAWN: Gonadotrophin-releasing hormone agonist protocols for pituitary desensitization in in vitro fertilization and gamete intrafallopian transfer cycles.

BACKGROUND: Gonadotropin releasing hormone agonists (GnRHa) are used in assisted reproduction cycles to reversibly block pituitary function and prevent a luteinizing hormone surge. In the short and ultrashort protocols of GnRHa administration, injection of gonadotropins is commenced a few days after the start of GnRHa. In the long protocols (with GnRHa started either in the midluteal phase or in the early follicular phase) gonadotropin administration is delayed until pituitary desensitization has been achieved, usually 2-3 weeks. OBJECTIVES: To conduct a systematic overview of available data comparing short or ultrashort and long GnRHa protocols for pituitary desensitization in in vitro fertilization (IVF) and gamete intra-fallopian transfer (GIFT) treatment cycles. SEARCH STRATEGY: Search strategies included on-line searching of the MEDLINE and EMBASE data bases and the Cochrane Menstrual Disorders and Subfertility Group's Specialised Register from 1982 to 1998, and hand searching of bibliographies of relevant publications and reviews, and abstracts of scientific meetings. SELECTION CRITERIA: Randomized trials of short or ultrashort versus long (follicular or luteal phase start) GnRHa protocols in IVF or GIFT treatment cycles. DATA COLLECTION AND ANALYSIS: Data were extracted into 2 x 2 tables. For the primary outcome, clinical pregnancy per cycle started, the overall common odds ratio (OR) and the risk difference with 95% confidence interval (CI) were calculated after verifying the presence of homogeneity of treatment effect across all trials. The following subgroup comparisons were performed: ultrashort versus long protocols, short versus long protocols and, within each of these comparisons, subgroups of studies which used the long protocol with follicular phase start or the long protocol with luteal phase start. Secondary outcomes considered were clinical pregnancy per oocyte retrieval and per embryo transfer, spontaneous abortion, ongoing/delivered pregnancy per cycle started, number of ampoules of gonadotropin used, number of oocytes retrieved, and fertilization rate. MAIN RESULTS: Twenty-six trials met the inclusion criteria. The common OR for clinical pregnancy per cycle started was 1.32 (95% CI , 1.10 - 1.57) in favour of the long GnRHa protocol. The studies were subgrouped, depending on whether, in the long protocol, the GnRHa was commenced in the follicular phase (8 trials) or luteal phase (16 trials). The respective ORs were 1.54 (95% CI, 1.11 - 2.13) and 1.21 (95% CI, 0.98 - 1.51). After excluding the four trials using the ultrashort protocol, the OR for long versus short protocols (22 trials) was 1.27 (95% CI, 1.04 - 1.56). A comparison of long versus ultrashort protocols (4 trials) produced an OR of 1.47 (95% CI, 1.02 - 2.12). AUTHORS' CONCLUSIONS: On the basis of clinical pregnancy rate per cycle started, this meta-analysis demonstrates the superiority of the long protocol over the short and ultrashort protocols for GnRHa use in IVF and GIFT cycles.

Sex-/ovarian steroid-dependent release of endomorphin 2 from spinal cord.

Mu-opioid receptor (MOR) agonists have been shown to be more potent analgesics in male than female rodents. Regulation of spinal MOR-coupled antinociception by 17beta-estradiol (estrogen, E2) and progesterone (P) is also sexually dimorphic; pregnancy levels of E2/P activate MOR-coupled analgesic pathways in male but not female rats. We hypothesized that the sexual dimorphic characteristics of MOR-coupled antinociception reflects sexual dimorphism in the regulation of the release from spinal cord of the endogenous MOR agonist, endomorphin 2 (EM2). Parameters of spinal EM2 release manifesting sexual dimorphism include its 1) magnitude: in vitro basal and K+-evoked release of EM2 from spinal tissue of male rats is approximately 50% greater than that observed from spinal cord of females; 2) modulation by ovarian sex steroids: E2/P treatment significantly enhanced K+-evoked EM2 release from spinal tissue of males, but not females; and 3) enhancement by opioid receptor blockade: naloxone enhanced stimulated EM2 release from spinal tissue of both males and females, but it augmented basal release from spinal tissue of only males. Enhancement of EM2 release by naloxone reflects negative coupling of MOR to EM2 release and hence its modulation by negative feedback since only activation of MOR, not kappa-or delta-opioid receptors, was able to inhibit evoked EM2 release. These data reveal that the EM2-MOR spinal analgesic system is more robust and "higher gain" in male versus female rodents. These findings could provide a mechanistic rubric for understanding the male female dichotomy in prevalence and intensity of chronic pain syndromes.

Penetrating keratoplasty: outcomes from a corneal unit compared to national data.

AIMS: To determine long term graft survival rates and visual results for different indications for penetrating keratoplasty from a single institution over 10 years and compare these to national outcome data. METHODS: Retrospective chart analysis. 784 records were available for review of 1096 consecutive penetrating keratoplasty procedures performed between 1990 and 1999 (72%). Outcomes of graft survival, visual acuity, and astigmatism were analysed and compared to national outcome data supplied by the UK Transplant Service. RESULTS: At 5 year follow up, overall graft survival was 66%. This was subdivided into 98% for keratoconus, 86% for viral keratitis, 85% for Fuchs' dystrophy, 84% for pseudophakic bullous keratopathy, 55% for regrafts, and 57% for other diagnoses. There was a significantly higher graft survival rate for all diagnostic subgroups except Fuchs' dystrophy at 3 years of follow up compared to the national average. Best corrected visual acuity at 5 years was 6/18 or better in 53% of cases. The mean keratometric astigmatism was 3.4 dioptres. CONCLUSION: Penetrating keratoplasty is a safe and effective treatment for selected corneal disorders. Penetrating keratoplasty for viral keratitis may achieve good results with long term antiviral treatment. Patients may achieve better outcomes if their surgery is performed at specialist centres.

Genetic polymorphism of the N-acetyltransferase 2 gene, and susceptibility to prostate cancer: a pilot study in north Indian population.

BACKGROUND: N-acetyltransferase 2 is phase II metabolizing enzyme that participates in the bioconversion of heterocyclic arylamines into electrophilic nitrenium ions, which are important ultimate carcinogens that are directly implicated in tumor initiation process. This study was conducted to examine; (1) whether the N-acetyltransferase 2 (NAT2) genotype is a risk factor for prostate cancer, (2) to study effect of NAT2 genotype on modifying prostate cancer risk from tobacco use. METHODS: The case control study was undertaken over a period of 28 months and included 130 prostate cancer patients (CaP) and 140 controls. The NAT2 genotypes were identified by PCR-RFLP method in DNA extracted from peripheral blood. Genotype frequencies and the association of genotypes with patients and control groups were assessed by logistic regression model. RESULTS: We observed non-significant association of rapid acetylator genotype NAT2 (OR = 1.452, 95% CI: 0.54-1.87, P = 0.136) in prostate cancer patients. However significant association was observed between rapid acetylator genotype NAT2 and CaP tobacco users (OR = 3.43, 95% CI: 1.68-7.02, P-value < 0.001) when compared with controls. CONCLUSION: The data suggests that the NAT2 rapid acetylator genotypes may play an important role in determining the risk of developing prostate cancer particularly in the tobacco users of north Indian population.

Melatonin generates singlet oxygen on laser irradiation but acts as a quencher when irradiated by lamp photolysis.

Melatonin, a naturally occurring chemical mediator, although assigned a diverse range of functions, has attracted interest in recent years because of its ability to function as a free radical scavenger. Because of the implications of singlet oxygen in neurotoxicity, the objective of the study was to investigate the ability of melatonin to quench singlet oxygen generated using laser irradiation or lamp photolysis. The results show that melatonin produces radicals upon laser irradiation while the lamp photolysis studies show that melatonin is able to scavenge singlet oxygen produced by naphthalene. While melatonin is a free radical scavenger under biological conditions, it acts as a generator of singlet oxygen and or radicals (as PhiDelta is 1.41) when irradiated with laser light, implying that it has the potential to be used in photodynamic therapy in the destruction of tumors.

NAT2 gene polymorphism in bladder cancer: a study from North India

PURPOSE: This study was conducted to examine: 1) whether the NAT2 genotypes are risk factors for bladder cancer, 2) to study possible association of tobacco usage with NAT2 genotype of these patients. MATERIALS AND METHODS: This case control study was undertaken over a period of 19 months and included 101 bladder cancer patients and 110 controls. The NAT2 genotypes were identified by PCR-RFLP method in peripheral blood DNA samples. Genotypes frequencies and the association of the genotypes among patients and controls group were assessed by chi2 test and Fisher exact test. RESULTS: The NAT2 fast acetylator genotype frequency of slow or fast acetylator genotypes was not significant in bladder cancer patients alone (OR = 1.18, 95 percent CI: 0.69 - 2.03, p value = 0.583) or combination with tobacco users (OR = 0.84, 95 percent CI: 0.328 - 2.125, p value = 0.813) when compared with controls. CONCLUSION: These data demonstrate that the NAT2 fast or slow acetylators genotype did not associated with the risk of developing bladder cancer in North Indian population when compared with controls.

Luteal phase support in assisted reproduction cycles.

BACKGROUND: The aspiration of the granulosa cells that surround the oocyte and the use of gonadotropin releasing hormone agonists (GnRHa) during assisted reproduction technology (ART) treatment can interfere with the production, during the luteal phase, of progesterone, which is necessary for successful implantation of the embryo. Providing hormonal supplementation during the luteal phase with either progesterone itself, or human chorionic gonadotropin (hCG), which stimulates progesterone production, may improve implantation and, thus, pregnancy rates. OBJECTIVES: To determine (1) if luteal phase support after assisted reproduction increases the pregnancy rate, (2) the optimal hormone for luteal phase support, i.e. hCG, progesterone, or a combination of both, and (3) the optimal route of progesterone administration. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1971 to Dec 2003), EMBASE (1985 to Dec 2003). We handsearched reference lists of relevant articles were scanned, and abstract books from scientific meetings up to December 2003. SELECTION CRITERIA: Randomized controlled trials of luteal phase support after ART treatment, comparing hCG or progesterone with placebo or no treatment, comparing progesterone with hCG, progesterone plus hCG, or progesterone plus estrogen, or comparing different routes of progesterone administration. Quasi-randomized trials were excluded from the main analyses, but included in a secondary analysis for each comparison. DATA COLLECTION AND ANALYSIS: For each comparison, data on live birth, ongoing and clinical pregnancy per embryo or gamete transfer procedure, miscarriage per clinical pregnancy, ovarian hyperstimulation syndrome (OHSS) per transfer, and multiple pregnancy per clinical pregnancy were extracted into 2 x 2 tables and subgrouped by use of GnRHa in the ovarian stimulation regimen. The odds ratio (OR) and risk difference (RD) were calculated. MAIN RESULTS: Fifty-nine studies were included in the review. Luteal phase support with hCG provided significant benefit, compared to placebo or no treatment, in terms of increased ongoing pregnancy rates (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.32 to 4.29) and decreased miscarriage rates (OR 0.12, 95% CI 0.03 to 0.50), but only when GnRHa was used. The odds of OHSS increased 20-fold when hCG was used in cycles with GnRHa. Progesterone use resulted in a small but significant increase in pregnancy rates (OR 1.34, 95% CI 1.01 to 1.79) when trials with and without GnRHa were grouped together, but no effect on the miscarriage rate was observed. No significant difference was found between progesterone and hCG or between progesterone and progesterone plus hCG or estrogen in terms of pregnancy or miscarriage rates, but the odds of OHSS were more than 2-fold higher with treatments involving hCG than with progesterone alone(OR 3.06, 95% CI 1.59 to 5.86). Comparing routes of progesterone administration, reductions in clinical pregnancy rate with the oral route, compared to the intramuscular or vaginal routes, did not reach statistical significance, but there was evidence of benefit of the intramuscular over the vaginal route for the outcomes of ongoing pregnancy and live birth. No significant difference in pregnancy rate was observed between vaginal progesterone gel and other types of vaginal progesterone. REVIEWERS' CONCLUSIONS: Luteal phase support with hCG or progesterone after assisted reproduction results in an increased pregnancy rate. hCG does not provide better results than progesterone, and is associated with a greater risk of OHSS when used with GnRHa. The optimal route of progesterone administration has not yet been established.

Penetrating keratoplasty: indications over a 10 year period.

AIMS: To determine the indications for penetrating keratoplasty (PK) at the Corneoplastic Unit and Eye Bank, UK, a tertiary referral centre, over a 10 year period. METHODS: Records of all patients who underwent PK at our institution between 1990 and 1999 were reviewed retrospectively. Of the 1096 procedures performed in this period, 784 records were available for evaluation (72%). RESULTS: Regrafting was the most common indication, accounting for 40.9% of all cases. Keratoconus was the second most common indication (15%), followed by Fuchs' endothelial dystrophy (9.3%), pseudophakic bullous keratopathy (7.6%), and viral keratitis (5.9%), which included both herpes simplex and herpes zoster and showed a statistically significant decreasing trend using regression analysis (p<0.005). Among the regraft subgroup, viral keratitis accounted for 21.2% as the underlying primary diagnosis. The most common cause for graft failure in the regraft subgroup was endothelial failure (41.8%). CONCLUSION: Regrafting is the leading indication for PK; viral disease-although declining-is the leading primary diagnosis.

NAT2 gene polymorphism in bladder cancer: a study from North India.

PURPOSE: This study was conducted to examine: 1) whether the NAT2 genotypes are risk factors for bladder cancer, 2) to study possible association of tobacco usage with NAT2 genotype of these patients. MATERIALS AND METHODS: This case control study was undertaken over a period of 19 months and included 101 bladder cancer patients and 110 controls. The NAT2 genotypes were identified by PCR-RFLP method in peripheral blood DNA samples. Genotypes frequencies and the association of the genotypes among patients and controls group were assessed by Chi2 test and Fisher exact test. RESULTS: The NAT2 fast acetylator genotype frequency of slow or fast acetylator genotypes was not significant in bladder cancer patients alone (OR = 1.18, 95% CI: 0.69 - 2.03, p value = 0.583) or combination with tobacco users (OR = 0.84, 95% CI: 0.328 - 2.125, p value = 0.813) when compared with controls. CONCLUSION: These data demonstrate that the NAT2 fast or slow acetylators genotype did not associated with the risk of developing bladder cancer in North Indian population when compared with controls.