Fatal Pulmonary Tumour Thrombotic Microangiopathy (PTTM) Associated with Signet Ring Cell Carcinoma of Colon: An Autopsy Diagnosis

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Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity in which the tumor cells embolize to the pulmonary vasculature leading to fibro cellular intimal thickening and arteriolar occlusion by cellular intimal proliferation. Sub-acute respiratory failure, pulmonary hypertension, right sided heart failure and sudden death may be seen due to consequences of stenosis of blood vessels.

We describe a case of a 23 year old man who presented with alleged history of found unconscious and declared brought death. He was clinically diagnosed as refectory sepsis with ventilator associated pneumonia with acute kidney injury. Past history revealed Crohn’s disease and treatment with Azathioprine and prednisolone. Mucicarmine was positive in colonic tumor as well as in pulmonary tumor cell emboli with recanalization and intimal fibro cellular proliferation of small arteries. A postmortem diagnosis of poorly differentiated signet ring cell carcinoma of colon with PTTM was made based on autopsy results.

Unfortunately, PTTM is difficult to diagnose and is mostly a post mortem diagnosis with an extremely poor prognosis. Pulmonary hypertension due to metastatic tumor emboli should be included in the differential diagnosis of various causes of dyspnea in patients with cancer.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity in which the tumor cells embolize, organize and recanalize to the pulmonary vasculature leading to fibro cellular intimal thickening and vessel stenosis. Sub-acute respiratory failure, pulmonary hypertension, right sided heart failure and sudden death may be seen due to consequences of stenosis of blood vessels caused by PTTM. In this report, we describe a rare case of PTTM associated with metastatic colon carcinoma diagnosed on postmortem examination of a young man. We also aim to review the literature related to PTTM and associated malignancies and how they were diagnosed and managed.

The Comparison of Muscle Timing between Athletes with and without Chronic Ankle Instability during Lateral Jump Landing

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Most studies have investigated peroneal reaction time in relevant conditions of unexpected inversion perturbation occurring. The need to conduct more functional and dynamic testing that closely mimics athletic performances has been emerged.The aim of present study was to compare premotor time and motor time of leg muscles between athletes with and without chronic ankle instability during landing phase of a lateral jump condition.Twelve athletes with self-reported unilateral chronic ankle instability and 12 matched controls participated in the study. Participants performed lateral jump landing test during a relatively simple dynamic choice reaction task.An electromyography device synchronized with a force plate collected data during the landing phase of lateral jump. Premotor time, motor time and reaction time of leg muscles were recorded and group differences were assessed.

Mean premotor time values for peroneus longus and tibialis anterior muscles were significantly (P=0.000, P= 0.035 respectively) greater in chronic ankle instability patients compared to controls. There was astatistically significant (p=0 .001, P= 0.014 respectively) decrease in motor time measures for peroneus longus and brevis muscles in chronic ankle instability group compared to control group. There was no statistically significant difference in reaction time between the 2 groups.This study found muscle timing deficits in injured ankles of athletes with chronic ankle instability compared to healthy ones. The greater premotor time delay of peroneus longus and tibialis anterior muscles demonstrated in subjects with ankle instability in compared to healthy athletes should be taken in to consideration during assessment and rehabilitation programs.

Ankle sprains are one of the most common injuries affecting athletes. Many ankle injuries are found in sports that require jumping and landing such as basketball, volleyball and soccer. Ankle sprains account for up to 25% of all lost time from participation in sport competitions. People who experience an ankle sprain are at risk of developing Chronic Ankle Instability (CAI) which is characterized by subjective, repeated episodes of giving way after an initial ankle sprain. It has been estimated that up to 80% of athletes experience a recurrent sprain. Symptoms of residual instability represent in 20-40% of patients and this can lead to osteoarthritis in long term. Proprioception, muscle strength, muscle reaction time, and postural control are the factors contributing to impaired neuromuscular control that is believed to be the main cause of ankle instability development.

Emergency Dialysis in End-Stage Renal Disease: Incidence and Characteristics in La Paz, Baja California Sur

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According to international guidelines of Kidney Disease: Improving Global Outcomes (KDIGO, 2012); chronic renal failure (CRF) is defined as those abnormalities of kidney structure or function, present for more than 3 months with implications for health. CRF is classified according to cause, category of glomerular filtration rate (GFR) and category of albuminuria. The estimated prevalence of CRF is 16.8% worldwide. CRF can progress to end-stage renal disease (ESRD), which requires dialysis or transplantation. However, many patients cannot undergo such therapies because of its high cost [2- 3].Complications of CRF include dialytic emergency, anemia, renal osteodystrophy and malnutrition, among others.

CRF is a highly prevalent pathology that affects people of all races, nationalities, age, gender and economic level. Low socioeconomic status and poor access to health services contribute to inequality in health care and exacerbate negative effects of genetic or biological predisposition [5-6]. It is precisely the people with little or no access to health services who are at greater risk for complications of CRF.

According to annual report of the United States Renal Data System, main causes of end-stage renal failure in patients with CRF are diabetes (153 cases per million inhabitants in 2009), arterial hypertension (99 cases per million inhabitants) and glomerulonephritis (23 cases per million inhabitants). Cardiovascular disease is also an important cause; however, about 28% of patients with clinically significant CRF (stage 3 or higher) are not diabetic or hypertensive, especially those older than 65 years. In developing countries, diabetes and hypertension are currently the leading causes of CRF with a prevalence of 30% and 21% respectively, but glomerulonephritis and CRF of unknown origin are responsible for a greater proportion of ESRD, especially in young patients.

In Mexico, CRF is one of main causes of morbidity and mortality and one of main causes of hospitalization in emergency departments. CRF is considered a catastrophic disease due to increasing number of cases, high investment costs, limited infrastructure and human resources, late detection and high morbidity and mortality rates in substitution programs. In Mexico, prevalence and incidence of patients with CRF is unknown and the precise number of patients in any of its stages, age groups and gender most affected is unknown. An incidence of 377 cases per million inhabitants and a prevalence of 1,142 per million is estimated. In Mexico there are about 52,000 patients on dialysis, of which 80% are treated at the Mexican Social Security Institute (IMSS).

Risk of Lactic Acidosis in Diabetic Patients Taking Metformin and Who Receive Intravascular Iodinated Contrast Media

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Due to thelarge number of patients who develop diabetes mellitus type 2 and the tendency to use radiological methods to avoid invasive procedures, it is becoming increasingly frequent to find patients undergoing metformin treatments who are being given intravascular iodinated contrast media. Traditionally, the fear that this can be linked to lactic acidosis has always existed, despite no proven evidence to support this theory.

The prevalence and incidence rate of diabetes mellitus type 2 is currently increasing; in most patients, the disease’s treatment is still based on the administering of metformin, along with a change of life style. Also, the number of patients who undergo radiological examinations, in which some form of intravascular iodinated contrast media is used, is increasing every day. Traditionally, metformin was withdrawn from those patients who needed to undergo studies involving intravascular iodinated contrast media due to the risk of developing lactic acidosis which, although not very frequent, has a very high mortality rate (40%). However, the evidence supporting this is based on isolated cases which have been researched using heterogeneous studies.

Intravascular iodinated contrast media are not a stand-alone risk factor of lactic acidosis in patients that take metformin, but rather they become relevant when other underlying kidney disorders are also present. Taking this into account, we can establish a causal link because the use of intravascular iodinated contrast media does suppose a risk of developing kidney failure; this risk can be stratified depending on each patient’s characteristics. According to this there is a possibility of developing contrast-induced nephropathy. A set of variables were established and given a value; according to the total sum, the risk of developing a nephropathy can be calculated. The variables were: systolic blood pressure below 80mmHg, intra-aortic balloon pump, grade 3-4 heart failure or a history of acute lung edema, being over 75 years of age, packed cell volume below 39% in men or below 36% in women, diabetes mellitus, contrast volume and glomerular filtration (which greatly affects the final assessment).

Guide for Morpholino Users: Toward Therapeutics

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Morpholino oligos are uncharged molecules for blocking sites on RNA. They are specific, soluble, non-toxic, stable, and effective antisense reagents suitable for development as therapeutics and currently in clinical trials. They are very versatile, targeting a wide range of RNA targets for outcomes such as blocking translation, modifying splicing of pre-mRNA, inhibiting miRNA maturation and activity, as well as less common biological targets and diagnostic applications. Solutions have been developed for delivery into a range of cultured cells, embryos and adult animals; with development of a non-toxic and effective system for systemic delivery, Morpholinos have potential for broad therapeutic development targeting pathogens and genetic disorders.

Morpholino oligos bind to complementary sequences of RNA and get in the way of processes. Morpholino oligos are commonly used to prevent a particular protein from being made in an organism or cell culture. Morpholinos are not the only tool used for this: a protein’s synthesis can be inhibited by altering DNA to make a null mutant (called a gene knockout) or by interrupting processes on RNA (called a gene knockdown). Some DNA alterations cause production of a protein to decrease without stopping all production; confusingly, these are also called gene knockdowns. DNA alterations are permanent, while knockdowns of RNA are either transient, generally last several days after dosing with antisense (such as Morpholinos), or are long-term, depending on continued production of knockdown RNA in cells (such as shRNA transcribed in cells from a plasmid).

Morpholinos have been broadly used in the developmental biology community to knock down genes in embryos of organisms such as zebrafish (Danio rerio), African clawed frogs (Xenopus sp.), chicks (Gallus gallus), sea urchins (e.g. Strongylocentrotus sp.), sea squirts (Ciona sp.), and many more. The oligos are usually microinjected though fine glass needles into early embryos at the one-to-few cell stage. Many kinds of antisense have toxic effects during development of an embryo. Because Morpholinos have little interaction with protein they are unusually non-toxic antisense, sufficiently non-toxic to make them the first choice of most developmental biologists for transient gene knockdowns. In contrast, injection of oligos containing phosophorothioate intersubunit linkages often kills embryos. Morpholinos are highly specific antisense, having less interaction with unintended RNAs than antisense which employs protein activity; this is because a Morpholino must be complementary to a longer sequence of RNA than antisense using catalytic activity (e.g. RNAi, phosphorothioate RNA, etc.). Less specific antisense causes changes in gene expression during development of the embryo and can cause developmental defects (teratogenesis).

Gastric Plication for Repeated Gastric Band Prolapse after Endoscopic Treatment: A Case Report

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Laparoscopic Adjustable Gastric Banding (LAGB) is a simple, safe and effective procedure for treating morbid obesity. However, several complications after LAGB have been reported, such as band erosion, prolapse, gastric perforation, abscess, tube disconnection, port flip down and infection.These complications could be the main cause of failure after LAGB. For this reason, revisional weight-loss surgery after failed LAGB might be considered. Band prolapse is a significant and common late complication after LAGB. We have performed endoscopic treatment of band prolapse as we reported.

However, band prolapse occurred repeatedly in two cases. We present a patient with repeated prolapses after endoscopic treatment that required gastric plication treatment. A 35-year-old woman with BMI (Body Mass Index) 40 underwent LAGB procedure to treat her obesity using the pars flaccida technique with no implication suture, and port placement under the anterior sheath of the rectus abdominis muscle. The patient presented a history of onset of band prolapse 22 months after the LAGB procedure. The symptoms of prolapse were sudden abdominal pain and repeated vomiting. An endoscopic procedure was performed after deflation of the band under intravenous anesthesia. Band prolapse was diagnosed and treated by endoscopy.

After a prolapsed stomach pouch was found, we inflated it with air. The prolapsed stomach pouch was gradually reduced as the stomach was inflated with air. The stomach was fully reduced and finally the band returned to its normal position. After reduction, the entire lumen of the stomach was examined to check its normality. However, the patient had the second episode of band prolapse that required endoscopic treatment five months after the first one. We treated it with the same endoscopic technique as above. The patient had recurrence that was treated by the endoscopic reduction technique 13 months after the second episode. The third endoscopic treatment of band prolapse was performed for an hour resulting in failure. She was sent to operating room and underwent laparoscopic reduction with two-row gastric plication. The gastric greater curvature was plicated using 2/0 prolen from fundus at the level of diaphragm preserving the His angle to 10cm proximal to the pylorus. It took 70min for the whole procedure with 3 trocars under general anesthesia. The patient was discharged in good condition 3 days after surgery. Fifteen months later, there was no evidence of recurrence.

Not all anterior band prolapses have reduced by band deflation and endoscopic approach. When we found any sign of infection or perforation inside the stomach, we fixed it operatively. Otherwise, almost all the band prolapses after such sutureless LAGB without delay in diagnosis can be fixed easily with an endoscopic procedure. Those patients with repeated band prolapses could be treated by onerow or two-row plication technique. The gastric greater curvature was plicated using 2/0 prolen from fundus at the level of diaphragm preserving the His angle to 10cm proximal to the pylorus. The aim of the plication was restriction of the prolapsed portion of the stomach via folds from its own wall. However, we need long term followup to evaluate the efficacy of the gastric plication and endoscopic treatment of the band prolapse.

Nanotechnology- A Promising Approach for Suicide Gene Therapy

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Cancer is one of the world’s most dreadful diseases and the battle against cancer continues till date. Suicide gene therapy for cancer is one of the best approaches for annihilation of cancer. In brief, suicide gene codes for an enzyme which converts a nontoxic prodrug into toxic metabolites and subsequently mediates death of host cells itself on account of which it is named “suicide” gene therapy. These suicide gene when constitutively expressed by the cells not only mediates death of host cells but also inflicts strong bystander effects on neighboring cells by predisposing them to toxic downstream metabolites. Due to such advantages, they manifest minimal systemic toxicity and are also effective against many drug resistance cancer cells. Among all existing suicide genes, Cytosine Deaminase (CD) and Herpes Simplex Virus-thymidine kinase (HSVtk) have shown promising results initially and has been investigated extensively since long. The HSVtk enzyme initially phosphorylates the prodrug Ganciclovir (GCV) to its monophosphate form, which is subsequently phosphorylated again by endogenous cellular kinase to generate nucleotide analogs (di- and triphosphate forms of GVC). Triphosphate form of GCV is then readily incorporated into DNA during the course of DNA synthesis and acts as a chain terminator to prevent further DNA synthesis, which ultimately induces cell death.

The therapeutic efficacy of HSVtk suicide gene therapy is often limited by cell-to-cell contact which is a prerequisite for transport of downstream metabolic byproducts of ganciclovir to neighboring cells so as to attain bystander-killing effect. As an outcome of such drawbacks, HSVtk suicide gene does not seem to be effective against different cell types. In contrary to this, Cytosine Deaminase (CD) efficiently converts prodrug 5-Fluorocytosine (5- FC) into therapeutically active anticancer agent 5-Fluorouracil (5- FU), which subsequently permeates across the cell membrane to mediate bystander killing effects on adjacent neighboring cells. Thus, 5-FC/CD system attains suicide gene therapy much more efficiently as compared to other counterparts. Although 5-FC/CD system attains better therapeutic outcomes, it is ineffective against 5-FC resistant cancer cells and thus its anticancer potential could not be generalized for all cancer types. In order to overcome such drawback, Gopinath et al. have designed Cytosine Deaminase-Uracil Phosphoribosyltransferase (CD-UPRT) bifunctional suicide gene construct in which Uracil Phosphoribosyltransferase (UPRT) acts upon product of CD i.e. 5-FU and converts it further into other toxic metabolites.

The therapeutic effect of suicide genes can be enhanced by combinatorial approaches. In combination therapy, two or more drugs with similar or different mode of action are employed to realize synergistic anticancer therapeutic potentials. Such synergistic anticancer potential of combination of radiation therapy and 5-FC/ CD plus UPRT gene therapy was demonstrated by Kambara et al. against malignant gliomas [8]. Apart from this, the combination therapy also provides scope for exploiting radio sensitizing properties of 5-FU and by stander effects during the course of treatment. Many research groups have reported the use of suicide gene in combination with chemotherapy and radiation to enhance the therapeutic effect and to overcome the drug resistance. Gopinath et al. were the first to report the applications of silver nanoparticles for synergizing the therapeutic effect of suicide gene. They have also reported the synergistic therapeutic effect of suicide gene with anticancer drug curcumin. One of the major challenging tasks in suicide gene therapy is lack of suitable vectors for targeted delivery of suicide gene to cancer cells. The application of such DNAbased therapeutics is largely limited due to poor cellular uptake, degradation by serum nucleases and rapid renal clearance following systemic administration. In addition to these, organ specific targeted DNA therapy has been a major challenge to overcome off-target gene therapy. In order to circumvent these limitations, numerous organ specific targeted nanocarriers have been developed recently for systemic administration.