Trick or Treat: An Intrahepatic Intraductal Papillary Neoplasm of the Bile Duct.

An intraductal papillary neoplasm involving the biliary tree is an unusual premalignant condition of epithelial origin, identified by its cystic dilatation of the biliary channels. Being a slow-growing tumor, surgery offers the best curative rate, especially in the setting of a low-grade disease. Here, we present a case of a localized, low-grade, intraductal papillary neoplasm of the bile duct (IPNB), residing in the liver, which was treated with resection of the liver lobe. The adjuvant treatment and prognosis highly depend upon the presence of dysplasia or a co-existent invasive malignancy. To the best of our knowledge, being a rare entity, this is the first case to be reported from Pakistan.

The Impact of Microbiota on the Gut-Brain Axis: Examining the Complex Interplay and Implications.

The association and interaction between the central nervous system (CNS) and enteric nervous system (ENS) is well established. Essentially ENS is the second brain, as we call it. We tried to understand the structure and function, to throw light on the functional aspect of neurons, and address various disease manifestations. We summarized how various neurological disorders influence the gut via the enteric nervous system and/or bring anatomical or physiological changes in the enteric nervous system or the gut and vice versa. It is known that stress has an effect on Gastrointestinal (GI) motility and causes mucosal erosions. In our literature review, we found that stress can also affect sensory perception in the central nervous system. Interestingly, we found that mutations in the neurohormone, serotonin (5-HT), would result in dysfunctional organ development and further affect mood and behavior. We focused on the developmental aspects of neurons and cognition and their relation to nutritional absorption via the gastrointestinal tract, the development of neurodegenerative disorders in relation to the alteration in gut microbiota, and contrariwise associations between CNS disorders and ENS. This paper further summarizes the synergetic relation between gastrointestinal and neuropsychological manifestations and emphasizes the need to include behavioral therapies in management plans.

Why is That Chin Numb? A Case of Burkitt's Lymphoma Presenting as Numb Chin Syndrome.

We report a case of numb chin syndrome (NCS) that preceded the diagnosis of Burkitt's lymphoma (BL) and discuss our findings with emphasis on metastatic malignancies in general and BL in particular causing NCS. A 73-year-old woman presented with worsening right-sided back pain for a week along with right-sided leg weakness and a progressive thigh and perianal numbness. She reported numbness of the chin which started two weeks prior. MRI showed compression of the cauda equina which was highly suggestive of neoplastic process. After debulking mass surgery, biopsy of the tissue from spine revealed BL. The patient received a round of radiotherapy of spine and multiple rounds of chemotherapy. Six months later she had reoccurrence of lymphoma with metastasis and eventually passed away. Presence of NCS in the setting of an underlying malignancy indicates very poor prognosis. In appropriate clinical setting, NCS should trigger work up for an underlying malignancy.

Complicated Isolated Liver Abscess Caused by Viridans Group Streptococci Leading to Right Hepatectomy.

Pyogenic liver abscesses (PLAs) secondary to bacterial etiologies are most often seen in developing countries and are less common in North America. The predominant etiology is infection occurring in the setting of direct extension of hepatobiliary or intestinal infection. The most common pathogen isolated from a PLA in the United States is Escherichia coli, whereas Streptococcus viridans is a rare entity in the developed world. Herein we report a rare case of a complicated isolated PLA in a patient without any known comorbidities which lead to hepatectomy. The patient was born and raised in the United States with no recent travel history. The patient was found to have 10 cm isolated multicystic mass on imaging confirmed later as vancomycin-resistant Streptococcus viridans PLA. The patient was treated with multiple intravenous antibiotics and underwent multiple ultrasound-guided percutaneous abscess drainages by interventional radiology, but all unsuccessful. The patient underwent right posterior liver lobectomy, thereafter making a quick recovery and was discharged. Our case underlines the significance of considering liver abscess as a differential even in previously healthy individuals with no known prior comorbid conditions, as prompt recognition is imperative in preventing morbidity and mortality.

Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages.

Only a single drug against schistosomiasis is currently available and new drug development is urgently required but very few drug targets have been validated and characterised. However, regulatory systems including cyclic nucleotide metabolism are emerging as primary candidates for drug discovery. Here, we report the cloning of ten cyclic nucleotide phosphodiesterase (PDE) genes of S. mansoni, out of a total of 11 identified in its genome. We classify these PDEs by homology to human PDEs. Male worms displayed higher expression levels for all PDEs, in mature and juvenile worms, and schistosomula. Several functional complementation approaches were used to characterise these genes. We constructed a Trypanosoma brucei cell line in which expression of a cAMP-degrading PDE complements the deletion of TbrPDEB1/B2. Inhibitor screens of these cells expressing only either SmPDE4A, TbrPDEB1 or TbrPDEB2, identified highly potent inhibitors of the S. mansoni enzyme that elevated the cellular cAMP concentration. We further expressed most of the cloned SmPDEs in two pde1Δ/pde2Δ strains of Saccharomyces cerevisiae and some also in a specialised strain of Schizosacharomyces pombe. Five PDEs, SmPDE1, SmPDE4A, SmPDE8, SmPDE9A and SmPDE11 successfully complemented the S. cerevisiae strains, and SmPDE7var also complemented to a lesser degree, in liquid culture. SmPDE4A, SmPDE8 and SmPDE11 were further assessed in S. pombe for hydrolysis of cAMP and cGMP; SmPDE11 displayed considerable preferrence for cGMP over cAMP. These results and tools enable the pursuit of a rigorous drug discovery program based on inhibitors of S. mansoni PDEs.

Periventricular Hyperintensities Mimicking Multiple Sclerosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small-to-medium-sized vessel disease that causes degeneration of vascular smooth muscles. The most frequently found mutation is NOTCH3 on chromosome 19, the presence of which confirms the diagnosis of CADASIL. The core features of CADASIL are migraine, ischemic events, cognitive decline, and psychiatric features. Its symptoms overlap with other diseases, most commonly with multiple sclerosis (MS). Both diseases can give fluid-attenuated inversion recovery in periventricular regions and deep white matter. CADASIL is often misdiagnosed and treated as MS due to these similarities. We present a case of a 28-year-old woman who began treatment for MS and was later confirmed with a diagnosis of CADASIL with a NOTCH3 mutation.

Fungal Cervical Abscess Complicated by Necrotizing Fasciitis Leading to Descending Necrotizing Mediastinitis: A Case Report.

Cervical necrotizing fasciitis (CNF) is a rapidly spreading deep neck infection with a high mortality rate if left untreated. The occurrence of necrotizing infections in the head and neck region is uncommon; therefore, it is a rare cause of chest pain presenting to the emergency department. Here, we present an interesting case of fungal cervical skin abscess complicated by necrotizing fasciitis that progressed to involve the mediastinum, causing necrotizing mediastinitis with pneumomediastinum in an elderly female. The patient presented to the emergency department with chest pain, shortness of breath, and fever. She had a 10-day history of a mass in the anterior midline of her neck with odynophagia. After radiologic confirmation, she was taken to the operating room where she underwent incision and drainage with debridement and washout. Postoperatively, she was given broad-spectrum antibiotics empirically, which were later replaced with intravenous (I/V) fluconazole after culture reports. Prompt diagnosis and treatment lead to the early recovery of the patient and subsequent discharge without any complications. We report this case to draw the attention of emergency medicine physicians and clinicians to this rare and life-threatening but treatable condition. Expeditious diagnosis and treatment lead to early recovery and fewer postoperative complications.

A fission yeast platform for heterologous expression of mammalian adenylyl cyclases and high throughput screening.

The fission yeast Schizosaccharomyces pombe uses a cAMP signaling pathway to link glucose-sensing to Protein Kinase A activity in order to regulate cell growth, sexual development, gluconeogenesis, and exit from stationary phase. We previously used a PKA-repressed fbp1-ura4 reporter to conduct high throughput screens (HTSs) for inhibitors of heterologously-expressed mammalian cyclic nucleotide phosphodiesterases (PDEs). Here, we describe the successful expression of all ten mammalian adenylyl cyclase (AC) genes, along with the human GNAS Gαs gene. By measuring expression of an fbp1-GFP reporter together with direct measurements of intracellular cAMP levels, we can detect both basal AC activity from all ten AC genes as well as GNAS-stimulated activity from eight of the nine transmembrane ACs (tmACs; AC2-AC9). The ability to use this platform to conduct HTS for novel chemical probes that reduce PKA activity was demonstrated by a pilot screen of the LOPAC®1280 library, leading to the identification of diphenyleneiodonium chloride (DPI) as an inhibitor of basal AC activity. This screening technology could open the door to the development of therapeutic compounds that target GNAS or the ACs, an area in which there is significant unmet need.

Ruptured Ectopic Pregnancy in an Accessory Horn of Uterus: A Case Report.

A unicornuate uterus with an accessory horn is one of the rarest congenital uterine anomalies; hence, the possibility of ectopic pregnancy in the accessory uterine horn is highly uncommon. It poses a significant risk to maternal life, as it is difficult to identify before surgery due to the severe hemoperitoneum in the event of rupture of the ectopic pregnancy. We report a case of a 20-year-old primigravida who presented to the emergency department of Civil Hospital Karachi, with sudden onset of generalized abdominal pain, vomiting, and dizziness at 17 weeks of gestation. Emergency ultrasonography of the abdomen showed extensive echogenic fluid, which was considerably obscuring the view. An empty uterus was seen with a complex cystic mass on its right side separate from the ovary. A ruptured ectopic pregnancy was suspected, and hence, the patient was immediately shifted to the operating room. Emergency laparotomy was done which then showed ruptured ectopic pregnancy with a viable fetus in a right-sided rudimentary horn of the uterus. The horn was excised. The patient recovered well, and the postoperative course was uneventful.

Canagliflozin and Cardiovascular disease- results of the CANVAS trial.

Canagliflozin is a new novel oral antidiabetic agent belonging to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors, inhibiting glucose reabsorption in the proximal tubule, leading to increased urinary glucose excretion and subsequently to reduction in plasma glucose concentration, in individuals with hyperglycemia. Before the approval of canagliflozin by the Food and Drug Administration (FDA) in 2013, a pair-wise meta-analyses of trials involving canagliflozin did not differ from control in terms of all-cause mortality, cardiovascular death, myocardial infarction, and stroke. However, no large, randomized-controlled trials were available for comparison until the results of the CANVAS (Canagliflozin Cardiovascular Assessment Study) trial were published. The CANVAS Trial was designed to assess the cardiovascular safety and efficacy of canagliflozin. Recently, results of the completed CANVAS Trial were released which showed patients with type 2 diabetes and established cardiovascular disease or at high risk for cardiovascular events who were treated with canagliflozin had significantly lower rates of the primary cardiovascular outcome than patients assigned to placebo. All three components of the primary outcome - death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke - showed point estimates of effect that suggested benefit .These results may represent a significant additional therapeutic tool in the clinical prevention and management of cardiovascular mortality and morbidity. However, data on the long-term efficacy on the use of Canagliflozin is still incomplete and their use in patients with type 2 diabetes should be carefully considered.

Canakinumab and cardiovascular outcomes: results of the CANTOS trial.

IL-1 cytokines are mainly responsible for controlling a series of pro-inflammatory reactions induced in response to pathogen mediated tissue injury. Among the IL-1 cytokine family, IL-1 ß results in upregulation of genes responsible for boosting immune system reactivity and inflammatory response. With growing pathophysiological relevance of IL-1ß in a myriad of disease pathogenesis, new biological drugs have been developed in recent years. One such drug, Canakinumab, targeting IL-1ß has been recently approved for clinical use. The recent results from the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial are encouraging in this aspect. The results suggest that anti-inflammatory therapy using canakinumab at a dose of 150 mg every 3 months led to significantly lower recurrent cardiovascular events than the placebo drug. These results were independent of lipid-lowering effects of these drugs. If the results are widely applicable, the CANTOS trial would reaffirm the hypothesis of atherothrombosis due to inflammation, hence supporting the need for a cytokine-based therapy for the secondary prevention of cardiovascular diseases. Moreover, the potential benefits of the phenomenal reduction in the inflammatory cascade induced by canakinumab should be carefully balanced against its long-term safety profile which is yet unknown. However, the inflammatory hypothesis of atherothrombosis supports a cytokine-based therapy for the secondary prevention of cardiovascular disease. Furthermore, the potential benefits from the reduction in inflammatory markers induced by canakinumab should be carefully balanced against its unknown long-term safety profile.

Perspective On Health Seeking Behavior Of Patients With Oropharyngeal Cancers From A Pakistani Background.

Oropharyngeal cancers are the most common cancers of head neck region, they are placed amongst the top ten malignancies globally and around 40% of all the cancers in South and South East Asia. Patient's personal behaviour impacts causality more than the environmental factors in the pathology and prognosis of this particular cancer. In our country risk factors are based on poor infrastructure of the health care system, illiteracy, poor socioeconomic status, Betel nut and quid, smokeless and smoke tobacco. We recommend that an active precautionary approach is required to restrict the rising incidence in the oral cancers, particularly due to culturally related risk habits and reluctance to seek early healthcare amongst our people. Primary prevention is the need of time.