Sub-therapeutic colchicine levels in a patient treated for acute pericarditis in the setting of carbamazepine use: A case report.

WHAT IS KNOWN AND OBJECTIVE: Colchicine is a standard therapy for the treatment of acute pericarditis. It is metabolized by cytochrome P-450 3A4 (CYP3A4) and is subject to potential drug interactions. Multiple case reports describe accumulation of colchicine with CYP3A4 inhibitors, but limited data exist for increased colchicine clearance with CYP3A4 inducers. We describe a case of idiopathic haemorrhagic pericarditis treated with colchicine but rendered ineffective given potential drug interaction with carbamazepine. CASE SUMMARY: A 61-year-old man with a history of seizures presented to the emergency department with severe chest pain radiating to the back and was found to have a large pericardial effusion. The patient underwent pericardiocentesis, which demonstrated a haemorrhagic pericardial effusion. After an extensive workup, he was treated for idiopathic pericarditis with anti-inflammatories and colchicine but failed to improve despite adequate colchicine loading and maintenance dosing. A serum colchicine level was checked given a potential CYP3A4 drug interaction in the setting of chronic carbamazepine use and was found to be sub-therapeutic. Concomitant use of CYP3A4 inducers in the setting of colchicine use can render anti-inflammatory strategies ineffective and may result in treatment failure. WHAT IS NEW AND CONCLUSION: Due to its hepatic and intestinal metabolism by CYP3A4 enzymes, colchicine is susceptible to drug-drug interactions resulting in either toxicities or rendering it ineffective with concomitant CYP3A4 inhibitors or inducers, respectively. Carbamazepine, a common anti-epileptic medication and known inducer of the CYP3A4 enzyme, may reduce levels of colchicine in the blood resulting in treatment failure. Further study is required to determine if dose adjustments may overcome this drug interaction.

Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages.

The mitochondria-to-nucleus retrograde signaling (MtRS) pathway aids in cellular adaptation to stress. We earlier reported that the Ca2+- and calcineurin-dependent MtRS induces macrophage differentiation to bone-resorbing osteoclasts. However, mechanisms through which macrophages sense and respond to cellular stress remain unclear. Here, we induced mitochondrial stress in macrophages by knockdown (KD) of subunits IVi1 or Vb of cytochrome c oxidase (CcO). Whereas both IVi1 and Vb KD impair CcO activity, IVi1 KD cells produced higher levels of cellular and mitochondrial reactive oxygen species with increased glycolysis. Additionally, IVi1 KD induced the activation of MtRS factors NF-κB, NFAT2, and C/EBPδ as well as inflammatory cytokines, NOS 2, increased phagocytic activity, and a greater osteoclast differentiation potential at suboptimal RANK-L concentrations. The osteoclastogenesis in IVi1 KD cells was reversed fully with an IL-6 inhibitor LMT-28, whereas there was minimal rescue of the enhanced phagocytosis in these cells. In agreement with our findings in cultured macrophages, primary bone marrow-derived macrophages from MPV17-/- mice, a model for mitochondrial dysfunction, also showed higher propensity for osteoclast formation. This is the first report showing that CcO dysfunction affects inflammatory pathways, phagocytic function, and osteoclastogenesis.-Angireddy, R., Kazmi, H. R., Srinivasan, S., Sun, L., Iqbal, J., Fuchs, S. Y., Guha, M., Kijima, T., Yuen, T., Zaidi, M., Avadhani, N. G. Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages.

Polymorphism and Expression Profile of Cholecystokinin Type A Receptor in Relation to Gallstone Disease Susceptibility.

In the present study, we investigated expression pattern of Cholecystokinin type A receptor (CCKAR) in relation to its commonly studied polymorphism (rs1800857, T/C) in gallstone disease (GSD) patients and controls. A total of 502 subjects (272 GSD and 230 controls) were enrolled, and genotyping was performed by evaluating restriction fragments of PstI digested DNA. For analyzing expression pattern of CCKAR in relation to polymorphism, gallbladder tissue samples from 80 subjects (GSD-55; control-25) were studied. Expression of CCKAR mRNA was evaluated by reverse transcriptase-PCR and confirmed using real-time PCR. Protein expression was evaluated by enzyme-linked immunosorbent assay. We observed significantly (p < 0.0001) lower expression of CCKAR mRNA and protein in GSD tissues as compared with control. Significantly higher frequency of A1/A1 genotype (C/T transition) (p = 0.0005) was observed for GSD as compared with control. Expression of CCKAR protein was found to be significantly lower (p < 0.0001) in A1/A1 genotype as compared with other genotypes for GSD patients. Perhaps, this is the first report providing evidence of alteration in CCKAR expression in relation to its polymorphism elucidating the molecular pathway of the disease. Additional investigations with lager sample size are needed to confirm these findings.

Prognostic significance of survivin in resected gallbladder cancer.

BACKGROUND: Survivin, a novel inhibitor of apoptosis, plays a role in oncogenesis and has been correlated with poor prognosis. We investigated its expression in gallbladder tissues of control, cholelithiasis, and gallbladder cancer (GBC). Survivin expression was correlated with different clinicopathologic parameters including prognosis in patients with GBC. MATERIALS AND METHODS: Gallbladder tissue samples were collected from GBC (n = 39), cholelithiasis (n = 30), and control (n = 25). Expression of survivin messenger RNA (mRNA) was evaluated by real time polymerase chain reaction. Protein quantification was done by enzyme-linked immunosorbent assay. RESULTS: Significantly higher expression of survivin mRNA was observed in GBC (2.9-fold) and cholelithiasis (1.85-fold) as compared with control (P < 0.0001). In GBC, increased survivin expression (mRNA and protein) was significantly associated with higher tumor stage (stage III versus stage II) (P < 0.0001) and poor tumor differentiation (poor and moderate versus well) (P < 0.0001). No significant correlation was observed with any of the other clinicopathologic factors studied. Increased expression of survivin was associated with shorter survival (median survival 11.5 mo versus 18 mo). CONCLUSIONS: Differential expression of survivin in GBC suggests its possible role in gallbladder carcinogenesis. Its overexpression is associated with poor prognosis. Assessment of survivin might be used to stratify GBC patients for optimal treatment modalities, including targeted therapy.

Expression of survivin mRNA in gallbladder cancer: a diagnostic and prognostic marker?

Survivin, an inhibitor of apoptosis, has been shown to be expressed in various malignancies. However, its role in gallbladder cancer (GBC) has not been evaluated yet. We investigated its expression in peripheral blood of patients with gallbladder diseases (gallstone disease (GSD), n = 30; GBC, n = 39) and compared with healthy controls (n = 25). Survivin expression was correlated with clinicopathological parameters, diagnosis, and prognosis of patients with GBC. Expression of survivin messenger RNA (mRNA) in blood was evaluated by real-time PCR. Significantly higher (P < 0.0001) expression of survivin mRNA was observed in GBC (2.2-fold) and GSD (1.52-fold) as compared to control. In GBC, increased survivin expression was significantly associated with higher tumor stage (stage III vs. stage II; P < 0.0001) and tumor differentiation (poor and moderate vs. well differentiated; P < 0.0001). No significant correlation was observed with any of the other clinicopathological parameters (age, gender, and presence or absence of gallstones) studied. Cutoff value of survivin mRNA relative quantification (RQ) was 1.08, with a sensitivity of 98.55 % and specificity of 100 % for the diseased group (GSD or GBC). RQ value of 1.71 differentiated GBC from GSD with a sensitivity of 89.74 % and specificity of 100 %. Increased expression of survivin was associated with a shorter median overall survival (12 vs. 18 months) in GBC patients. Differential expression of survivin in GBC suggests its possible role and association with poor prognosis. Expression of survivin in peripheral blood could be useful both in the diagnosis and prognosis of GBC.

Prognostic significance of K-ras codon 12 mutation in patients with resected gallbladder cancer.

BACKGROUND: Point mutation of K-ras is associated with carcinogenesis and overall survival in various cancers. We investigated the mutational spectrum of K-ras codon 12 in resected normal and gallbladder cancer tissue samples in a Northern Indian population and correlated it with different clinicopathological parameters. PATIENTS AND METHODS: Gallbladder tissues from normal (n = 24) and cancer patients (n = 39) were analyzed for K-ras codon 12 mutation by restriction fragment length polymorphism. Statistical analysis was carried out using the χ(2) test or Fisher's exact test. Survival was estimated using the Kaplan-Meier method, and the difference between survival curves was analyzed by the log-rank test. RESULTS: The frequency of K-ras mutation was significantly higher (p = 0.001) in gallbladder cancer tissue samples (16/39) compared to normal samples (1/24). Patients with K-ras mutation had a significantly decreased overall survival (p = 0.003), particularly for stage II (p = 0.021) and III (p = 0.009) cancers. No significant correlation was observed with any of the other clinicopathological factors studied. CONCLUSIONS: Gallbladder cancer has a high frequency of K-ras codon 12 mutation with poorer outcomes in resected stage II and III disease. K-ras mutational analysis has important prognostic implications that need to be investigated further.

Heterodimerization of cholecystokinin 1 and cholecystokinin 2 receptors in gallbladder cancer: a new mechanism for carcinogenesis.

PURPOSE: Cholecystokinin is present in abundance in gallbladder tissue and mediates function through two structurally related receptors, CCK1R and CCK2R. Heterodimerization of these receptors is known to impact cell growth in vitro. However, the significance of these heterodimers in gallbladder carcinogenesis is relatively unknown. METHODS: Therefore, we evaluated the expression and the dimerization status of CCK1 and CCK2 receptors in human gallbladder carcinoma cell line (GBC-SD) and resected gallbladder tissue from normal (n = 10), cholelithiasis (n = 25) and gallbladder cancer (n = 25) by immunofluorescence/immunohistochemistry and western blot. The dimerization status of CCK1R and CCK2R was evaluated by co-immunoprecipitation. To understand the effect of heterodimerization of these receptors on growth-related signaling pathways, the expression of p-AKT, rictor, raptor and p-ERK was evaluated by western blot. RESULTS: We demonstrated the expression and heterodimerization of CCK1 and CCK2 receptor in GBC-SD gall bladder carcinoma cell line. Knockdown of CCK1R and CCK2R in the cell line led to significant reduction in p-AKT (P = 0.005; P = 0.0001) and rictor (P < 0.001; P < 0.001) levels. In tissue samples, significantly higher expression of CCK1R and CCK2R was observed in gallbladder cancer when compared to other groups both by immunohistochemistry (P = 0.008 and P = 0.013) and western blot (P = 0.009 and P = 0.003). An increase in heterodimer formation of CCK1R with CCK2R was observed in gallbladder cancer when compared to normal and cholelithiasis tissues. No significant difference in the expression of p-AKT and p-ERK was observed between the three groups. CONCLUSION: Our results provide the first evidence of heterodimerization of CCK1R and CCK2R in gallbladder tissue, and its association with development of gallbladder cancer. This finding has potential clinical and therapeutic significance.

Interferon-gamma signaling promotes melanoma progression and metastasis.

Interferon-gamma (IFNG) has long been regarded as the flag-bearer for the anti-cancer immunosurveillance mechanisms. However, relatively recent studies have suggested a dual role of IFNG, albeit there is no direct experimental evidence for its potential pro-tumor functions. Here we provide in vivo evidence that treatment of mouse melanoma cell lines with Ifng enhances their tumorigenicity and metastasis in lung colonization allograft assays performed in immunocompetent syngeneic host mice, but not in immunocompromised host mice. We also show that this enhancement is dependent on downstream signaling via Stat1 but not Stat3, suggesting an oncogenic function of Stat1 in melanoma. The experimental results suggest that melanoma cell-specific Ifng signaling modulates the tumor microenvironment and its pro-tumorigenic effects are partially dependent on the γδ T cells, as Ifng-enhanced tumorigenesis was inhibited in the TCR-δ knockout mice. Overall, these results show that Ifng signaling may have tumor-promoting effects in melanoma by modulating the immune cell composition of the tumor microenvironment.

Interferon-gamma induces melanogenesis via post-translational regulation of tyrosinase.

Melanogenesis (melanin pigment production) in melanocytes is canonically stimulated by the alpha melanocyte stimulating hormone (αMSH), which activates the cyclic-AMP-mediated expression of the melanocyte inducing transcription factor (MITF) and its downstream melanogenic genes, including the principal rate-limiting melanogenic enzyme tyrosinase (TYR). Here, we report that interferon-gamma (IFNG; type II interferon), but not interferon-alpha (a type I interferon), induces a noncanonical melanogenic pathway in mouse and human melanocytic cells. Inhibition of IFNG pathway by the JAK1/2 inhibitor ruxolitinib or knocking out Stat1 gene abrogated the IFNG-induced melanogenesis. Interestingly, IFNG-induced melanogenesis was independent of MITF. IFNG markedly increased the TYR protein expression but did not affect the mRNA expression, suggesting a post-translational regulatory mechanism. In contrast, IFNG had no effect on the expression of other melanogenesis-related proteins, for example, tyrosinase-related protein 1 (TYRP1) and dopachrome tautomerase (DCT). Glycosidase digestion assays revealed that IFNG treatment increased the mature glycosylated form of TYR, but not its de novo synthesis. Moreover, cycloheximide chase assay showed that degradation of TYR was decreased in IFNG-treated cells. These results suggest that the IFNG-STAT1 pathway regulates melanogenesis via regulation of the post-translational processing and protein stability of TYR.

Silicon tube frontalis suspension in simple congenital blepharoptosis.

BACKGROUND: Ptosis is an abnormally low position of the upper eyelid. Congenital ptosis should be corrected in early years of childhood. The aim of this study was to assess the efficacy and complications of frontalis suspension using silicon tube for simple congenital blepharoptosis with poor levator function. METHODS: A prospective study was performed on 33 children who underwent frontalis suspension using silicon tube from Jan 2008 to Jun 2011 with a minimum of 6 month follow-up. Functional success was defined when 3 criteria were met: (a) satisfactory lid height defined as margin-to-reflex distance > or = 3.5 mm with minimal frontalis action (brow up); (b) satisfactory lid symmetry (< or = 2 mm asymmetry in margin-to-reflex distance) between two lids; and (c) satisfactory cosmesis, i.e., normal lid contours. RESULTS: The mean follow-up duration was 9 months (range 6.5-27 months). The functional success rate was 91.4% (32/35 eyes). Three eyes had complications. In one eye (2.8%), recurrence of ptosis due to slippage of knot was seen, one eye developed infection of tract, and one with bilateral ptosis developed abnormal tenting of one of the lid. CONCLUSION: In simple congenital ptosis with poor levator function, frontalis suspension using silicon tube has good efficacy and an excellent safety profile. The results of frontalis suspension using silicon tube are comparable to fascia lata and superior to other non-autogenous materials.

Complications of nose and paranasal sinus disease.

BACKGROUND: Diseases of nose and paranasal sinuses can complicate to involve the orbit and other surrounding structures because of their close proximity. These diseases are usually infective or can be neoplastic in origin. METHOD: All the patients presenting in ENT or Eye Departments of Ayub Teaching Hospital during the one year study period who had complicated nose or paranasal sinus disease were included in the study. A detailed history and examination followed by CT scanning and laboratory investigations to assess the type and extent of the disease, was carried out. RESULTS: Infections were the most common cause of complicated sinus disease 11 (75%). The rest of the 4 (25%) cases were tumours. 12 (80%) of the cases presented with proptosis. In I of these 12 cases. there was complete blindness. In 2 (13%) of the cases there was only orbital cellulitis. Two of these patients had facial swelling and 2 had nasal obstruction and presented as snoring. Two patients presented with history of weight loss and these patients had malignant tumour of the paranasal sinuses. One patient presented with early signs of meningitis. In 1 case subperiosteal scalp abscess (Pott's puffy tumour) was the only complication noted. CONCLUSION: Nose and paranasal sinus diseases can complicate to involve mostly the orbit, but sometimes brain, meninges and skull bones can also get involved.

Use of Systemic Bivalirudin and an Anticoagulant-Free Purge Solution in a Percutaneous Left Ventricular Assist Device in a Patient With Heparin-Induced Thrombocytopenia.

The use of systemic bivalirudin and an anticoagulant-free purge solution in a percutaneous left ventricular assist device (pVAD) is described in a patient with a history of heparin-induced thrombocytopenia (HIT). An 80-year-old man with a past medical history of severe aortic stenosis and HIT was transferred to our facility for cardiogenic shock. The patient was emergently taken to the cardiac catheterization laboratory for balloon valvuloplasty and Impella pVAD (Abiomed, Inc) implantation. Due to the history of HIT, bivalirudin was chosen as an alternative anticoagulant. The device representative suggested adding bivalirudin 20 mg/500 mL to the Impella purge solution. However, due to the negligible amount of bivalirudin this would provide in comparison to patient's systemic intravenous bivalirudin dose, we elected not to add bivalirudin to the purge solution. The patient remained on the Impella for 72 hours with intravenous bivalirudin without any evidence of pump thrombosis as evidenced by unchanging flows and stable purge pressures. Unfortunately, despite functional Impella pVAD support, care was withdrawn due to ongoing multi-organ failure. This patient case demonstrated the safe, effective, and practical use of an anticoagulant-free purge solution with systemic bivalirudin in a patient with 72 hours of Impella support.

COVID-19 pandemic: Challenges and solutions from the cardiology pharmacist's perspective.

The recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges pharmacists worldwide. Alongside other specialized pharmacists, we re-evaluated daily processes and therapies used to treat COVID-19 patients within our institutions from a cardiovascular perspective and share what we have learned. To develop a collaborative approach for cardiology issues and concerns in the care of confirmed or suspected COVID-19 patients by drawing on the experiences of cardiology pharmacists across the country. On March 26, 2020, a conference call was convened composed of 24 cardiology residency-trained pharmacists (23 actively practicing in cardiology and 1 in critical care) from 16 institutions across the United States to discuss cardiology issues each have encountered with COVID-19 patients. Discussion centered around providing optimal pharmaceutical care while limiting staff exposure. The collaborative of pharmacists found for the ST-elevation myocardial infarction patient, many institutions were diverting COVID-19 rule-out patients to their Emergency Department (ED). Thrombolytics are an alternative to percutaneous coronary intervention (PCI) allowing for timely treatment of patients and decreased staff exposure. An emergency response grab and go kit includes initial drugs and airway equipment so the patient can be treated and the cart can be left outside the room. Cardiology pharmacists have developed policies and procedures to address monitoring of QT prolonging medications, the use of inhaled prostacyclins, and national drug shortages. Technology has allowed us to practice social distancing, while staying in close contact with our teams, patients, and colleagues and continuing to teach. Residents are engaged in unique decision-making processes with their preceptors and assist as pharmacist extenders. Cardiology pharmacists are in a unique position to work with other pharmacists and health care professionals to implement safe and effective practice changes during the COVID-19 pandemic. Ongoing monitoring and adjustments are necessary in rapidly changing times.

Bleeding Risks in Patients on Percutaneous Ventricular Assist Devices Receiving Two Different Dextrose Concentrations of Heparinized Purge Solution: A Case Series.

BACKGROUND: The Impella manufacturer has changed its recommendation for the diluent of the heparinized purge solution from 20% dextrose (D20) to 5% dextrose (D5). This reduced viscosity may result in increased purge solution infusion rates and unfractionated heparin (UFH) exposure. Increased UFH exposure could potentially cause increased bleeding events and may necessitate reduction in UFH concentration in the purge solution. Our objective was to evaluate anticoagulation for patients on Impella pumps receiving heparinized purge solution with D20 or D5 diluents. METHODS: This retrospective cohort analysis evaluated patients requiring Impella support outside of the cardiac catheterization lab. The primary outcome evaluated the number of patients with at least one supratherapeutic activated partial thromboplastin time (aPTT) while receiving heparinized purge solution alone without systemic UFH. Secondary outcomes included heparin concentration changes made to the purge solution, bleeding, and thrombotic events. RESULTS: Twelve patients received Impella support for an average of 37 hours (range, 10.8-89.6). Four patients received D20 and 8 patients received D5 purge solution. Five patients had at least one supratherapeutic aPTT while receiving heparinized purge solution alone without additional systemic UFH. All 5 patients were in the D5 group. Of these 5 patients, 3 required purge heparin concentration decreases and 3 had bleeding events. No patients had pump thrombosis. CONCLUSION: D5 purge solution with heparin 50 units/mL may increase the risk of supratherapeutic aPTTs, leading to increased bleeding. Decreasing heparin to 25 units/mL as a standard in purge solution may decrease these risks; however, protection against thrombosis remains unknown.

Significance of methylation status of MASPIN gene and its protein expression in prognosis of gallbladder cancer.

AIM: We investigated prognostic significance of methylation status of MASPIN gene and its protein expression in normal subjects, cholelithiasis and gallbladder cancer (GBC) patients. METHODS: MASPIN protein expression and its promoter methylation in gallbladder tissue of cholelithiasis (n = 36), GBC (n = 46) and controls (n = 25) were investigated. Clinicopathological parameters and prognosis of patients with GBC were correlated with protein expression of MASPIN. Survival analysis of GBC patients was performed using Kaplan-Meier method. RESULTS: Significant increased (P < 0.0001) protein expression of MASPIN was observed in GBC as compared to cholelithiasis, whereas negligible expression was found in normal tissues. Methylation-specific PCR revealed statistical significant (P = 0.005) difference in methylation status of MASPIN promoter between gallstone and GBC patients. Significant association was observed between methylation profile with protein expression of MASPIN (P = 0.004), stage (P = 0.011) and cellular differentiation (P = 0.012) for GBC. Also, significant (P = 0.004) difference in survival was observed for malignant patients having demethylated MASPIN promoter. Further significant negative correlation (Pearson's coefficient [r] = -0.617; P < 0.0001) was observed between MASPIN expression and survival of cancer patients after surgery. Overall survival was significantly shorter (P ≤ 0.0001; hazard ratio [HR] for death = 2.84; 95% confidence interval [CI], 0.09865-0.3683) in patients of GBC with MASPIN expression ≥169.56 pg/mg (median survival; 10 months) with compared to those with expression <169.56 pg/mg (median survival; 16 months). CONCLUSION: Overexpression of MASPIN protein may play an important role in malignant progression and is correlated with a poor prognosis. Also MASPIN DNA methylation can be used as a novel therapeutic target for treating GBC.

Epigenetic Mechanisms and Events in Gastric Cancer-Emerging Novel Biomarkers.

Gastric cancer is one of the most common malignancy worldwide. The various genetic and epigenetic events have been found to be associated with its carcinogenesis. The epigenetic is a heritable and transient/reversible change in the gene expression that is not accompanied by modification in the DNA sequence. This event is characterized by the alteration in the promoter CpG island of the gene or histone modification. These events are associated with silencing of critical tumor suppressor gene and activation of oncogenes leading to carcinogenesis. The DNA methylation is a chemical change in the DNA sequence that most commonly occurs at cytosine moiety of CpG dinucleotide and histone, primarily on N- terminal tail that ultimately effect the interaction of DNA with chromatin modifying protein.Hypermethylation of tumor suppressor genes and global hypomethylation of oncogenes are widely studied epigenetic modifications. There are large number of publish reports regarding epigenetic events involving gastric cancer. These changes are potentially useful in identifying markers for early diagnosis and management of this lethal malignancy. Also, role of specific miRNAs and long non coding RNAs in regulation of gene expression is gaining interest and is a matter of further investigation. In this review, we aimed to summarize major epigenetic events (DNA methylation) in gastric cancer along with alteration in miRNAs and long non coding RNAs which plays an important role in pathology of this poorly understood malignancy.

Status of children in blind schools in the northern areas of Pakistan.

BACKGROUND: Prevalence of blindness in Pakistan is estimated to be 0.9%, which comes to about 1.25 million persons. A significant number of these are persons under 20 years of age. To make these children useful citizens in future, special facilities are to be provided to these children for their education and training. A study was done to find out the visual status of the students studying in a blind school in Abbottabad, Pakistan, the only such facility in the region. METHOD: A total of 50 patients were examined during our visit to the blind school in Abbottabad. Age of the patients ranged from 6 to 27 years (mean: 12.32 years). All the students, who were otherwise healthy, were included in the study. RESULT: The most common disorder identified was malformed globe or traumatic eyes (16 cases, 32%), in most of the cases, leading to phthisis bulbi. Other conditions noticed were Retinitis Pigmentosa (10 cases, 20%), Keratoconus, Optic atrophy, Buphthalmos (6 cases each, 12%), corneal opacity (4 cases, 8%) and retinal detachment (2 cases 4%). CONCLUSION: We should work towards betterment of these schools by providing them with more funds, equipment and manpower. Regular visits of Ophthalmologists to these schools may be helpful. Genetic counselling should be arranged for the families.

An unusual case of bloody tears.

Conjunctival bleeding is usually caused by non accidental or accidental conjunctival laceration, conjunctival tumors and nasolacrimal sac tumors. We report here a rare case of conjunctival bleeding which was self induced using cinnamon bark.

A let-7 microRNA binding site polymorphism in the KRAS 3'UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population.

PURPOSE: Gallbladder cancer is a lethal malignancy of hepato-biliary system with high incidence in North India, especially along gangetic plain. The let-7 microRNAs play a key role in regulating KRAS expression and a polymorphism in 3' untranslated region (rs61764370, T/G) of KRAS leads to its higher expression. This polymorphism is known to be associated with increased risk and prognosis of various cancers but its association with gallbladder cancer has not been evaluated. To address this research question, we evaluated whether rs61764370 variant is associated with gallbladder cancer susceptibility and clinical outcomes. METHODS: In present case-control study, we enrolled 541 patients with gallbladder malignancy and 307 controls. Genomic DNA was obtained from peripheral blood and genotyping was performed using Taqman allelic discrimination assay. RESULTS: Heterozygous (TG) individuals are at a significant higher risk for GBC as compared with wild genotype (TT) (p = 0.007, odds ratio = 2.56, 95 % CI 1.27-5.18). At allelic level, allele G has significant higher risk for GBC as compared with T allele (p = 0.008, odds ratio = 2.5, 95 % CI 1.25-5.01). Survival analysis reveals decrease in overall survival for heterozygous genotype (p < 0.0001, hazard ratio = 3.42, 95 % CI 1.21-4.20). Also, significant decrease in overall survival was observed for patient carrying allele G (p < 0.0001, HR = 2.89, 95 % CI 1.21-4.20) as compared with allele C. CONCLUSIONS: We conclude that KRAS rs61764370 polymorphism is significantly associated with risk and prognosis of gallbladder malignancy in this endemic belt.

Frequency of ocular complications of leprosy in institutionalized patients in NWFP Pakistan.

BACKGROUND: There is no systemic disease, which so frequently gives rise to disorders of the eye as leprosy does. The study was conducted to determine the prevalence and gravity of ocular complications in institutionalized leprosy patients in NWFP. It is important to provide necessary information to leprosy health workers and general physicians in order to sensitize them to early detection and treatment or referral to appropriate centre. METHODS: A prospective study of ocular complications of leprosy patients was conducted at the leprosy centre of Lady Reading Hospital Peshawar and the Leprosy Hospital Balakot, district Mansehra. The study included a record of the name, age, sex, type, duration of disease and completion of multi-drug therapy (MDT). Classification of the patients was done according to Ridley and Jopling 5-group system. Visual acuity was tested by Snellen chart and those patients having a vision of less than 3/60 were labelled as blind. Ocular adnexa were examined by naked eye and lacrimal sac regurgitation test was done. Slit lamp biomicroscopy was done for anterior segment examination and direct ophthalmoscope was used for fundoscopy. RESULTS: The authors studied 143 patients in the above mentioned leprosy centres. Out of these, 59 had lepromatous leprosy, 39 borderline tuberculoid leprosy, 9 tuberculoid leprosy, 33 borderline lepromatous leprosy, and 33 borderline leprosy. The majority of patients came from the northern districts of NWFP, including Malakand division and district Mansehra. The male to female ratio was 4:1. The age of the patients ranged from 14 to 80 years and the duration of the disease ranged from 1 year to 48 years. Ocular complications were found in 73% of the patients. These complications included loss of eyebrows in 57 patients, loss of eyelashes in 37, corneal changes (including opacity, ulceration, and/or anaesthesia) in 44, iridocyclitis in 31, lagophthalmos in 36, ectropion in 13, and chronic dacryocystitis in 3. Of the total of 15 (11%) patients who went blind from ocular complications, 16 eyes did so due to corneal opacities, 6 eyes due to cataract, 5 eyes due to chronic anterior uveitis and one eye due to corneal ulcer, panophthalmitis and phthisis bulbi each. CONCLUSIONS: A significant number of leprosy patients (73%) have ocular complications. The frequency of ocular complications increases with the increasing age and duration of disease of the patients.