Comparative study of the clinico-trichoscopic response to treatment of hirsutism with long pulsed (1064 nm) Nd:YAG laser in idiopathic hirsutism and polycystic ovarian syndrome patients.

Treatment of hirsutism is usually resistant, and from medical management to laser hair reduction, the treatment of hirsutism and its assessment are the most challenging. The aim of the study was to compare the response to treatment by laser hair reduction with long pulsed (1064 nm) Nd:YAG laser in patients of idiopathic hirsutism and polycystic ovarian syndrome (PCOS) by clinical and trichoscopic assessment. A hospital-based comparative, observational prospective study was carried out on female patients with hirsutism over a period of 18 months with two groups of participants: fifty women with idiopathic hirsutism (group A) and fifty with PCOS (group B). Laser hair reduction was done with long pulsed (1064 nm) Nd:YAG laser in both groups up to six sessions, 4 weeks apart and followed for 3 months post last laser session. After the sixth session of laser hair reduction, excellent response (> 75% reduction) from baseline was seen in 70% of patients in group A and in 54% of patients in group B. After 3 months of follow-up of the last laser session, it was found that the results persisted in patients with idiopathic cause than in those due to PCOS, seen both clinically and trichoscopically with decrease in hair shaft thickness, hair shaft colour, terminal vs. vellus hair ratio and hair density per cm2. Hirsutism due to idiopathic cause responds better to laser hair reduction with long pulsed (1064 nm) Nd:YAG laser than that due to PCOS, due to underlying hormonal imbalance in the latter group. Follow-up of only up to 3 months after last laser session was done and tricoscan was not done.

Hepatitis A infection during pregnancy.

QUESTION: Many of my patients are from Southeast Asia, where hepatitis A virus (HAV) infection is quite common. What precautions can I suggest my pregnant patients take before traveling to these areas and what is the risk of contracting HAV during pregnancy? ANSWER: Hepatitis A virus is a water-borne pathogen transmitted by the fecal-oral route. To reduce the risk of contracting HAV while traveling to endemic areas, it is important to maintain hygienic practices such as hand washing with safe water, particularly before handling food, avoiding drinking water or using ice cubes of unknown purity, and avoiding eating unpeeled fruits and vegetables. An HAV vaccine is available and can be administered before traveling to endemic countries. Hepatitis A virus infection has a largely favourable expected outcome even during pregnancy. Infection occurring in the second or third trimester has been reported to be associated with preterm labour.

Hepatitis E infection during pregnancy.

QUESTION: Many of my patients are from Southeast Asia where hepatitis E virus (HEV) infection is quite common. What precautions can I suggest they take before traveling to these areas and what is the risk of contracting HEV during pregnancy? ANSWER: Hepatitis E is a water-borne pathogen transmitted by the fecal-oral route. To reduce the risk of contracting HEV while traveling to endemic areas, it is important to maintain hygienic practices such as hand washing with safe water, particularly before handling food, avoiding drinking water or using ice cubes of unknown purity, and avoiding eating unpeeled fruits and vegetables. Currently there is no vaccine available in Canada for HEV. Hepatitis E infection during pregnancy, especially in the third trimester, is characterized by a more severe infection that sometimes results in fulminant hepatitis, increasing maternal and fetal mortality and morbidity.

Synthesis and activity of three new trinuclear platinums with cis-geometry for terminal metal centres.

BACKGROUND: As compared to cisplatin, trinuclear platinum compounds such as BBR3464 and DH6Cl have an altered spectrum of activity possibly because they form long-range adducts with DNA as against mainly intrastrand 1,2-bifunctional adducts formed by cisplatin and its analogues. Because of the labilizing effect associated with the trans-geometry, the compounds are expected to break down inside the cell thus serving to reduce the number of long-range adducts formed. In contrast, trinuclear platinum complexes with cis-geometry for the terminal metal centres would be less subject to such breakdown and hence may produce a greater number of long-range inter- and intrastrand adducts with the DNA. This paper describes the synthesis and activity against human ovarian tumour models of of three new trinuclear platinum complexes with cis-geometry for terminal platinum centres, coded as QH4, QH7 and QH8. The paper also describes cellular accumulation of platinum, level of drug-DNA binding, and nature of interaction of the compounds with pBR322 plasmid DNA. RESULTS: Methods of synthesis, elemental analysis, spectral studies and molar conductivity measurements provide support to the suggested structures of the compounds. QH4 and QH8 are found to be more cytotoxic than cisplatin against the parental A2780 cell line; QH8 is more active than cisplatin against the resistant A2780cisR and A2780ZD0473R cell lines as well. The least compound QH7 shows a greater activity against the resistant cell lines than the parental cell line; it is most damaging to pBR322 plasmid DNA and most able to induce changes in DNA conformation. The variations in activity of the compounds, changes in intracellular drug accumulation and levels of Pt-DNA binding with the changes in number of planaramine ligands bound to central platinum and the length of the linking diamines, can be seen (1) to illustrate structure-activity relationships and (2) to highlight that the relationship between antitumour activity and interaction with cellular platinophiles including DNA can be quite complex as the cell death is carried out by downstream processes in the cell cycle where many proteins are involved. CONCLUSION: Among the three designed trinuclear platinum complexes with cis-geometry for the terminal metal centres, the most active compound QH8 is found to be more active than cisplatin against the parental A2780 and the resistant A2780cisR and A2780ZD0473R cell lines.

Serum Lipid and Leptin Concentrations in Patients with Sheehan Syndrome.

BACKGROUND: Sheehan syndrome (SS) refers to the occurrence of hypopituitarism after parturition. Hypopituitary adults with growth hormone (GH) deficiency have abnormal body composition with increased fat mass. As leptin is secreted almost exclusively by fat cells and the circulating leptin level is proportional to total fat mass, it is expected that abnormal elevations of leptin concentrations are found in GH deficient hypopituitary patients. The present study was undertaken to evaluate the anthropometric, lipid and leptin levels in patients with SS. MATERIALS AND METHODS: Thirty patients with SS and 30 age and body mass index (BMI) matched controls were part in this study. All patients were stable on conventional replacement therapy for at least 6 months before the study. The subjects underwent detail clinical, biochemical, and hormone analysis. RESULTS: Patients with SS on conventional replacement therapy showed significantly higher mean triglyceride, total cholesterol, low density lipoprotein cholesterol and lower high density cholesterol concentrations. The leptin levels were significantly raised in the patients with SS on standard replacement therapy compared with controls. The difference was more marked in obese cases versus obese controls than in lean cases and controls (P = 0.001). CONCLUSION: SS, a cause of GH deficiency. Our study demonstrated that patients with SS have an abnormal lipid profile, and raised leptin levels as compared to age and BMI matched controls.

Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression.

BACKGROUND: Diabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. METHODS: We screened nine genetic variations in three cytokine genes (TNF-α, IL-6 and IL-ß) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). RESULTS: Individual SNP analysis showed highest association of IL-1ß rs16944-TT genotype (OR = 3.51, 95%CI = 2.36-5.21, P = 0.001) and TNF-α rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64-4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3-14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%CI = 15.1-28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-α expression was increased by more than four-folds (n-fold = 4.43 ±â€¯1.11) in DN. TNF-α, IL-6 and IL-1ß transcript levels were significantly modulated by promoter region SNPs. CONCLUSIONS: The present study implicates a strong association between cytokine TNF-α, IL-6 and IL-1ß gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects.

Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition.

Diabetes mellitus is increasing at an alarming rate and has become a global challenge. Insulin resistance in target tissues and a relative deficiency of insulin secretion from pancreatic ß-cells are the major features of type 2 diabetes (T2D). Chronic low-grade inflammation in T2D has given an impetus to the field of immuno-metabolism linking inflammation to insulin resistance and ß-cell dysfunction. Many factors advocate a causal link between metabolic stress and inflammation. Numerous cellular factors trigger inflammatory signalling cascades, and as a result T2D is at the moment considered an inflammatory disorder triggered by disordered metabolism. Cellular mechanisms like activation of Toll-like receptors, Endoplasmic Reticulum stress, and inflammasome activation are related to the nutrient excess linking pathogenesis and progression of T2D with inflammation. This paper aims to systematically review the metabolic profile and role of various inflammatory pathways in T2D by capturing relevant evidence from various sources. The perspectives include suggestions for the development of therapies involving the shift from metabolic stress to homeostasis that would favour insulin sensitivity and survival of pancreatic ß-cells in T2D.

Synthesis and antitumour activity of a new trinuclear platinum compound [{cis-PtCl(NH3)2µ {trans-Pt(3-hydroxypyridine)2H2N(CH2)5NH2)2}] Cl4 in human ovarian cancer cells.

A trinuclear platinum compound with a cis-geometry for the terminal metal centers coded as QH5 has been synthesized and investigated for activity against the human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cancer cell lines. Cellular accumulation of platinum, level of platinum-DNA binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH5 is found to be more active than cisplatin against all the three cell lines and to have much lower resistant factors than cisplatin. The compound is 2.5-times more active than cisplatin against the A2780(cisR) cell line and 11.5-times more active than cisplatin against A2780(ZD0473R) cell line. When the activity of QH5 in A2780 cell line is compared with its activity in the A2780(ZD0473R) cell line, it is found to be 2.4-times more active against the resistant A2780(ZD0473R) cancer cell line than the parent A2780 cell line, thus indicating that it has been able to overcome mechanisms of resistance operating in the A2780(ZD0473R) cell lines. The higher activity of QH5 as compared to cisplatin is found to be associated with higher platinum accumulation at all time points and high level of platinum-DNA binding at 24 h in all the three human ovarian cancer cell lines. Provided QH5 has the right toxicity profile and its in vitro activity is complemented with sufficient activity in vivo, the compound may have the potential for development as a novel platinum-based anticancer drug targeted to ovarian cancer.

CTTTA Deletion/Insertion polymorphism in 3'-UTR of LEPR gene in type 2 diabetes subjects belonging to Kashmiri population.

BACKGROUND: Type 2 diabetes mellitus is a multi-factorial disease in which both genetic and non-genetic factors interact in order to precipitate the diabetic phenotype. Among various predisposing genetic loci, a pentanucleotide (CTTTA) Del/Ins variant in the 3'-UTR of the LEPR gene is associated with type 2 diabetes and its related traits. This study was done to explicate for the first time the association of this Del/Ins polymorphism of LEPR gene in type 2 diabetes patients belonging to the ethnic population of Kashmir valley. METHODS: 670 unrelated subjects comprising of 320 type 2 diabetes patients and 350 healthy controls were included in the study. Genotyping of the untranslated region of LEPR gene encompassing this Del/Ins variant was done by PCR-RFLP technique and results were validated by direct sequencing. RESULTS: Genotype frequencies for both type 2 diabetes cases and healthy controls were consistent with Hardy-Weinberg equilibrium (χ(2) = 3.09 and 2.37, P = NS). The Del/Del genotype was predominantly found in cases than controls (P = 0.003, OR: 0.62, CI: 0.45-0.85). Carriers of Ins/Ins genotype were relatively protected against the risk factors (P = 0.0004, OR: 0.31, 95% CI: 0.15-0.61). A positive association was observed between the Del allele and the risk factors of type 2 diabetes. CONCLUSION: The results elucidate that the CTTTA Del allele is a genotypic risk factor of type 2 diabetes in the Kashmiri population.

Assessing efficient patient care: should length of stay be calculated independently of local admission rates?

OBJECTIVE: To compare the length of hospitalisation for infants with bronchiolitis across the Eastern region and to assess the impact of the varying admission rates in each hospital. DESIGN: Data collection through the Hospital Episode Statistics (HES) using the ICD clinical coding for bronchiolitis across all hospitals in east of England for three winter seasons (October to March for the years 2009/10, 2010/11 and 2011/12). MAIN OUTCOME MEASURE: Length of hospital stay, corrected to adjust for local population. RESULTS: Seventeen hospitals across the east of England were included in this study. Overall admission rate (as a percentage of the population) for the region was 3.3% and consistent with national data, but rates within individual hospitals varied between 1.5% and 5.7% over the 3-year period. Bed days per 1000 population ('standardised bed days') per year varied almost fourfold, from 34.5 to 122.3 in different hospitals. Corrected length of stay showed high discordance when compared to average length of stay. CONCLUSIONS: The average length of stay is substantially affected by admission rates, with hospitals who admit a greater proportion of infants appearing to have a shorter uncorrected length of stay. We propose that a single corrected measure for length of stay should be used when assessing the efficiency of care because it is unaffected by variations in local admission rates and is adjusted for local population size.

Tissue transglutaminase antibody levels predict IgA deficiency.

OBJECTIVE: Measuring serum tissue transglutaminase immunoglobulin A (tTG IgA) levels is the most widely used screening test for coeliac disease. However, given an increased prevalence of IgA deficiency among coeliac patients there is a risk of false negative results. Hence, in addition to specific serum tTG IgA, screening tests frequently include total IgA levels. The objective of this study was to determine whether tTG IgA antibody levels might be used to predict IgA deficiency and hence avoid unnecessary testing of total IgA levels in all individuals. DESIGN: Retrospective analysis of 9429 serum tTG IgA and corresponding total IgA levels obtained from children and young adults in the East of England between 2007 and 2011. RESULTS: The overall prevalence of IgA deficiency was found to be very low with only 0.9% of individuals affected. Using receiver operating characteristic curve analysis we identified a cut-off value for tTG IgA of ≥0.10 µ/mL to be predictive for the absence of total IgA deficiency (IgA<0.06 g/L). Specifically, using this cut-off value, total IgA deficiency could be excluded with a sensitivity of 0.92 and specificity of 0.84. In our cohort, only 16.4% of our patient sample would have needed total IgA measurement to rule out a false negative result due to IgA deficiency. CONCLUSIONS: Our data provide a simple means of avoiding unnecessary total IgA measurements in the assessment of coeliac disease. By using tTG IgA value quantitatively, only values <0.10 µ/mL require total IgA measurements to rule out IgA deficiency and hence a potentially false negative screening result.

Pregnancy and pituitary disorders: Challenges in diagnosis and management.

Pregnancy is associated with normal physiological changes in endocrine system that assists fetal survival as well as preparation of labor. The pituitary gland is one of the most affected organs in which major changes in anatomy and physiology take place. Due to overlapping clinical and biochemical features of pregnancy, sometimes the diagnosis of pituitary disorders may be challenging. It is important to know what normal parameters of changes occur in endocrine system in order to diagnose and manage complex endocrine problems in pregnancy. In our present review, we will focus on pituitary disorders that occur exclusively during pregnancy like Sheehan's syndrome and lymphocytic hypophysitis and pre-existing pituitary disorders (like prolactinoma, Cushing's disease and acromegaly), which poses significant challenge to endocrinologists.

Recovery of prolactin function following spontaneous pregnancy in a woman with Sheehan's syndrome.

Sheehan's syndrome (SS) presents with hypopituitarism after parturition, usually preceded by postpartum hemorrhage. The first symptom of the disorder is lactation failure because of lactotroph cell necrosis. Recovery of lactotroph function after initial insult has not been reported in the literature. We describe the evaluation of a case of SS in whom lactotroph function recovered after the second pregnancy. A young woman delivered her first child at the age of 25 years; delivery was followed by severe postpartum hemorrhage and required blood transfusion. Sheehan's syndrome was diagnosed because of lactotroph, corticotroph, thyrotroph and somatotroph failure and empty sella on MRI. She conceived twice spontaneously and had normal lactation after the second delivery; investigations confirmed the normal basal and stimulable prolactin levels. We presume that recovery of lactotroph function after the second pregnancy in a patient with SS is possibly because of stimulatory effect of estrogen and progesterone on residual lactotroph cells.

A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk.

BACKGROUND: Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety. METHODS AND FINDINGS: Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines. CONCLUSIONS: The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity.

Synthesis and activity of [{Cis-PtCl(NH3)2}2µ{trans-Pt(3-Hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in the human ovarian tumour models.

A novel trinuclear platinum compound with a cis-geometry for terminal metal centres coded as QH1 has been synthesized, characterized and investigated for activity against the human ovarian A2780, A2780cisR and A2780ZD0473R cancer cell lines. The cellular accumulation of platinum, level of platinum-DNA binding and the nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH1 is found to be more active against the resistant cell lines than the parent cell line, thus indicating that the compound has been able to overcome mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. The high activity of QH1 is associated with high platinum accumulation and high level of platinum-DNA binding in all the three ovarian cancer cell lines. Provided QH1 has the right toxicity profile and its in vitro activity is matched with sufficient activity in vivo, the compound has the potential for development as a novel platinum-based anticancer drug targeted to the ovarian cancer.