Unveiling the Anti-Cholera and Active Diabetic Renoprotective Compounds of Maqian Essential Oil: A Computational and Molecular Dynamics Study.

Cholera is an exceptionally aggressive infectious disease characterized by the potential to induce acute, copious, watery diarrhea of considerable severity and renal inflammation. Diabetic nephropathy is a serious complication of diabetes mellitus that can lead to kidney failure through inflammation; thus, anti-inflammatory agents are promising therapies for diabetic nephropathy. Previous studies have shown that the essential oil of Zanthoxylum myriacanthum var. pubescens Huang, Maqian essential oil (MQEO), exhibits potent antibacterial, anti-inflammatory, and renoprotective activities in diabetic mice and has emerged as a potential therapeutic drug for the treatment of diabetic nephropathy complications. Therefore, the present study was carried out to screen the potential inhibition of cholera toxin and the diabetic renoprotective activity of MQEO through computational approaches. Twelve chemical constituents derived from MQEO were docked with cholera toxin and the target proteins involved in diabetic nephropathy, namely, TXNIP, Nrf2, and DPP IV, and, subsequently, the predictions of molecular dynamic simulations, the drug-likeness properties, and the ADMET properties were performed. α-terpineol showed high binding affinities toward the cholera toxin protein. For TXNIP, among all the chemical constituents, α-phellandrene and p-cymene showed strong binding affinities with the TXNIP protein and displayed relatively stable flexibility at the hinge regions of the protein, favorable physicochemical properties in the absence of hepatotoxicity, and low cytotoxicity. For Nrf2, α-terpineol exhibited the highest binding affinity and formed a very stable complex with Nrf2, which displayed high pharmacokinetic properties. All compounds had low free-binding energies when docked with the DPP IV protein, which suggests potent biological activity. In conclusion, based on a computational approach, our findings reveal that MQEO constituents have inhibitory activity against cholera toxin and are promising therapeutic agents for suppressing diabetic inflammation and for the treatment of diabetic nephropathy complications.

Non-O1/non-O139 Vibrio cholerae bacteraemia in mainland China from 2005 to 2019: clinical, epidemiological and genetic characteristics.

In mainland China, the clinical, epidemiological and genetic features of non-O1/non-O139 Vibrio cholerae (NOVC) bacteraemia have been scarcely investigated. Herein, we describe a patient with NOVC bacteraemia diagnosed in our hospital and present a retrospective analysis of literature reports of 32 other cases in China, detailing the clinical epidemiology, antibiotic resistance and molecular characteristics of isolates. Most patients were male (84.8%; median age, 53 years) and had predisposing factors, such as cirrhosis, malignant tumours, blood diseases and diabetes. In addition to fever, gastroenteritis was the most frequent presenting symptom. The mortality rate during hospitalisation was 12.1%. NOVC bacteraemia cases were more common in June-August, with the majority in coastal provinces and the Yangtze River basin. Only 42.4% of cases were attributed to consumption of marine (aquatic) products. Tetracycline, third-generation cephalosporins, and fluoroquinolones were the most effective antimicrobial agents, and the highest frequencies of resistance were recorded for ampicillin/sulbactam (37.5%), amoxicillin/clavulanic acid (33.3%), ampicillin (29.2%) and sulfamethoxazole (20%). Multi-drug resistant isolates were not detected. Limited data indicate that ctxAB and tcpA genes were absent in all NOVC isolates but other putative virulence genes (hlyA, toxR, hap and rtxA) were common. Ten multilocus sequence types were identified with marked genetic heterogeneity between different isolates. As clinical manifestations of NOVC bacteraemia may vary widely, and isolates exhibit genetic diversity, clinicians and public health experts should be alerted to the possibility of infection with this pathogen because of the high prevalence of liver disease in China.

Caracterización de las complicaciones de los pacientes diagnosticados con cólera en el Hospital Pediátrico de Centro Habana, 2013-2017 / Characterization of the complications of patients diagnosed with cholera in the Pediatric Hospital of Centro Habana, 2013-2017

Introducción: La séptima pandemia del cólera llegó a las Américas en 1991. En Cuba hacía más de 130 años no se registraba ningún caso. Objetivos: Identificar y caracterizar las complicaciones por cólera y su relación con características clínicas y de tratamiento. Métodos Se realizó un estudio descriptivo y prospectivo desde el año 2013-2017 a los pacientes a los que se les confirmó el V. cholerae como causa exclusiva de enfermedad diarreica aguda. Las variables cualitativas se describieron estadísticamente mediante frecuencias absolutas y relativas y para las variables cuantitativas se utilizó la media, la mediana, la desviación estándar y el rango intercuartílico como medidas de dispersión. Resultados: El 36,5 por ciento de los enfermos presentó complicaciones donde la deshidratación fue la más frecuente. El valor de la mediana del tiempo que medió entre la aparición de los síntomas y la atención en el centro fue menor en los pacientes con complicaciones comparado con el observado en los no complicados, pero la diferencia no fue significativa: (24 horas [RI: 24,0-72,0 horas] vs. 48 horas [RI: 24,0-72,0 horas], p= 0,355). Conclusiones: La mayoría de los enfermos no presentaron complicaciones y la más frecuente es la deshidratación ligera(AU)

Introduction: The seventh cholera pandemic arrived to the Americas in 1991. In Cuba for more than 130 years there were no case reports. Objectives: To identify and characterize the complications by cholera and its relation with clinical characteristics and treatment. Methods: A descriptive and prospective study was conducted from 2013 to 2017 to the patients who had been confirmed with V. cholerae as exclusive cause of acute diarrheal disease. The qualitative variables were described statistically using absolute and relative frequencies, and for the quantitative variables were used the average, medium, and standard deviation and the interquartile range as dispersion measures. Results: 36.5 percent of the patients presented complications where dehydration was the most frequent. The value of the median time between the onset of symptoms and attention in the center was lower in patients with complications in comparison with the observed in non-complicated patients, but the difference was not significant (24.0 h [RI: 24,0-72,0 h] vs. 48,0 h [RI: 24,0-72,0 h], p= 0.355). Conclusions: Most of the patients did not present complications and the most frequent is the slight dehydration (AU)

Vibrio cholera and V. parahaemolyticus coinfection in an oncology patient with gastroenteritis.

Vibrio-related gastroenteritis in the United States is mostly associated with the consumption of raw or improperly cooked seafood. We describe a case of a stage IV lung adenocarcinoma patient who became ill after eating crab while visiting Upstate New York. Molecular testing and culture confirmed a coinfection with V. parahaemolyticus and a nontoxigenic strain V. cholera.

Bacteriemia por Vibrio cholerae no-O1/no-O139 que porta una región homóloga a la isla de patogenicidad VpaI-7 / Bacteremia caused by Vibrio cholerae non-O1/non-O139 carrying a region homologous to pathogenicity island VpaI-7

Resumen Presentamos un caso de bacteriemia por Vibrio cholerae no-O1/ no-O139 en una mujer de 81 años con un cuadro de dolor abdominal, fiebre, vómitos, diarrea, coluria e ictericia, mientras visitaba una zona rural sin acceso a agua potable. La identificación se realizó por la técnica de espectrometría de masa MALDI-TOF, confirmándose una cepa no toxigénica no-O1/no-139. La caracterización molecular del aislado demostró la ausencia del gen de la toxina del cólera (CTX), y pilus TCP; sin embargo, presentó cinco de los seis genes de virulencia presentes en la isla de patogenicidad homóloga denominada VPaI-7 del V. parahaemolyticus (vcs N2+, vcs C2+, vcs V2+,toxR-, vspD+, T vopF+). Además, el aislado presentó los genes de virulencia hylA y rtxA. Este es el primer caso reportado en Chile de una cepa clínica de V. cholerae no-O1, no-O139 aislada de hemocultivos portador de un segmento homólogo de la isla de patogenicidad denominada VPaI-7 de V. parahaemolyticus, el cual codifica para un sistema de secreción tipo III (TTSS), que probablemente contribuye a su virulencia.

We report a case of V. cholerae non-O1 / non-O139 bacteremia in an 81-year-old woman with abdominal pain, fever, vomiting, liquid stools, choluria and jaundice, while visiting a rural area without access to potable water. The identification was made by the MALDI-TOF mass spectrometry technique and subsequently the non-toxigenic non-O1 / non-139 strain was confirmed in the national reference laboratory. The molecular characterization demonstrated the absence of the cholera toxin gene (CTX), and the TCP pilus, however, presented 5 of 6 virulence genes present in an island of homologous pathogenicity named VPaI-7 of V. parahaemolyticus (vcs N2 +, vcs C2 +, vcs V2 +, toxR-, vspD +, T vopF +) and in addition it was positive for hylAy rtxA virulence genes recognized outside the island. This is the first case reported in Chile of a clinical strain of V. cholerae non-O1, non-O139 isolated from blood culture that carries in its genome a homologous segment of the pathogenicity island named VPaI-7 of V. parahaemolyticus, which codifies for a type III secretion system (TTSS) that probably contributes to his virulence.

Bacteremia por Vibrio cholerae NO-O1/NO-O139 en un paciente cirrótico: Primer reporte de caso en el Perú y revisión de la literatura / Vibrio cholerae NO-O1/NO-O139 bacteremia in a cirrhotic patient: First case report in Peru and literatura review

Vibrio cholerae serogrupo NO-O1/NO-O139 (VCNO) es causa infrecuente de gastroenteritis. Sin embargo, se le asocia a infección extra-intestinal severa en huéspedes inmunocomprometidos, y entre ellas, la bacteremia en pacientes con cirrosis hepática es digna de mención. A continuación, presentamos el caso de una mujer de 58 años, con el diagnóstico de cirrosis hepática de fondo, que desarrolló progresivamente choque séptico, disfunción orgánica múltiple y desenlace fatal al cuarto día de su admisión. Los resultados obtenidos post mortem, de los hemocultivos previamente tomados, aislaron bacilos gram negativos compatibles con Vibrio cholerae. Posteriormente, se identificó el serogrupo NO-O1/NO-O139, a través de aglutinación en placa y PCR negativo para el gen ctxA. El antibiograma mostró susceptibilidad conservada a ampicilina, cloranfenicol, tetraciclina y ciprofloxacino, con resistencia al trimetoprim-sulfametoxazol. El presente caso, descrito en el Hospital Nacional Dos de Mayo, es hasta la fecha, el primer reporte de bacteremia VCNO en el Perú.

Non-O1, non-O139 Vibrio cholerae (NOVC) strains are an uncommon cause of gastroenteritis. However, they have been recently associated with severe extraintestinal infections in immunocompromised hosts. Among them, bacteremia in cirrhotic patients is noteworthy. We present the case of a 58-year-old woman with cirrhosis that developed septic shock, multiple organ failure and died four days after admission. Blood cultures yielded Gram-negative rods identified as Vibrio cholerae. Further serogrouping by slide agglutination and a negative PCR for ctxA gen confirmed the strain to be NOVC. Antimicrobial susceptibility testing showed sensitivity to ampicillin, chloramphenicol, tetracycline and ciprofloxacin; and resistance to trimethoprim-sulfamethoxazole. To the best of our knowledge, this is first report in Peru, described in the Hospital Nacional Dos de Mayo, of NOVC bacteremia.

Control de foco de un brote de Cólera. Matanzas 2014 / Control of Focus in front of a Bud of Cholera. Matanzas 2014

Se presenta un estudio de control de foco de un brote de cólera, mediante la técnica observacional del tipo serie de casos, en el mes de julio de 2014 en el Municipio Matanzas, donde se describe, según el método epidemiológico, la relación de los casos detectados con el caso índice; se analiza el problema detectado teniendo en cuenta el enfoque de riesgo del cólera. Se realiza una evolución clínico-epidemiológica de los casos detectados y se analizan las medidas de control de foco aplicadas. Se revisan tanto las historias clínicas individuales en el consultorio del médico de la familia, como las encuestas epidemiológicas y el expediente de control de foco en el departamento de Epidemiología (AU).

A study of control of focus of a bud of cholera is presented, by means of the observational technique of the type series of cases, in the month of July of 2014 in the Municipality Matanzas, where it is described, according to the epidemic method, the relationship of the cases detected with the index case; the detected problem is analyzed keeping in mind the focus of risk of the cholera. He/she is carried out a clinical-epidemic evolution of the detected cases and of the applied measures of focus control. They are revised the clinical histories so much in the clinic of the doctor of the family, as the epidemic surveys and the file of focus control in the department of epidemiology (AU).

Prevalence of Vibrio cholerae O1 serogroup in Assam, India: A hospital-based study.

BACKGROUND & OBJECTIVES: Although cholera remains to be an important public health problem, studies on reliable population-based estimates of laboratory confirmed cholera in endemic areas are limited worldwide. The aim of this hospital-based study was to evaluate the prevalence of Vibrio cholerae serogroup in Assam, India, during 2003-2013. METHODS: Stool samples/rectal swabs were collected from acute watery diarrhoea (AWD) cases during 2003-2013 and processed by standard microbiological procedures. Antibiotic sensitivity test was done following the Clinical and Laboratory Standards Institute guidelines. Year-wise epidemiological trend of cholera was analyzed. RESULTS: Cholera contributed to 3.93 per cent of AWD cases. In Assam, cholera was found to be more prevalent in the rural areas (6.7%) followed by the tea gardens (5.06%), urban slum (1.9%) and urban areas (1.4%). Highest proportion of cholera (13.7%) was observed in 0-10 yr age group. Of them, 11.5 per cent belonged to 0-5 yr age group. V. cholerae O1 El Tor serotype Ogawa was the predominant isolate. Multiple drug-resistant isolates of V. cholerae O1 Ogawa were reported in the study. INTERPRETATION & CONCLUSIONS: Emergence of resistance amongst V. cholerae towards many antibiotics is a matter of concern. Hence, continuous surveillance for diarrhoeal disorders is necessary to control the future outbreaks of cholera in this region.

The Effect of Solar Irradiated Vibrio cholerae on the Secretion of Pro-Inflammatory Cytokines and Chemokines by the JAWS II Dendritic Cell Line In Vitro.

The use of solar irradiation to sterilize water prior to its consumption has resulted in the reduction of water related illnesses in waterborne disease endemic communities worldwide. Currently, research on solar water disinfection (SODIS) has been directed towards understanding the underlying mechanisms through which solar irradiation inactivates the culturability of microorganisms in water, enhancement of the disinfection process, and the health impact of SODIS water consumption. However, the immunological consequences of SODIS water consumption have not been explored. In this study, we investigated the effect that solar irradiated V. cholerae may have had on the secretion of cytokines and chemokines by the JAWS II dendritic cell line in vitro. The JAWS II dendritic cell line was stimulated with the different strains of V. cholerae that had been: (i) prepared in PBS, (ii) inactivated through a combination of heat and chemical, (iii) solar irradiated, and (iv) non-solar irradiated, in bottled water. As controls, LPS (1 µg/ml) and CTB (1 µg/ml) were used as stimulants. After 48 hours of stimulation the tissue culture media from each treatment was qualitatively and quantitatively analysed for the presence of IL-1α, IL-1ß, IL-6, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, MIP-1α, MIP-1ß, MIP-2, RANTES, TNF-α, IL-23 and IL-27. Results showed that solar irradiated cultures of V. cholerae induced dendritic cells to secrete significant (p<0.05) levels of pro-inflammatory cytokines in comparison to the unstimulated dendritic cells. Furthermore, the amount of pro-inflammatory cytokines secreted by the dendritic cells in response to solar irradiated cultures of V. cholerae was not as high as observed in treatments involving non-solar irradiated cultures of V. cholerae or LPS. Our results suggest that solar irradiated microorganisms are capable of inducing the secretion of pro-inflammatory cytokines and chemokines. This novel finding is key towards understanding the possible immunological consequences of consuming SODIS treated water.

Fatal diarrheal disease caused by Vibrio cholerae O67 in a patient with myelodysplastic syndrome.

A 71-year-old man with myelodysplastic syndrome (MDS) receiving treatment with azacitidine developed extensive watery diarrhea for three consecutive days. As a result of high-grade dehydration, the patient was urgently admitted to the hospital and fluid replacement therapy was initiated. However, the patient's diarrhea did not improve. Vibrio cholerae non-O1/non-O139 was detected in a fecal culture. On the fourth day, the patient died due to circulatory collapse. An autopsy revealed extensive necrosis of the intestinal mucosa. Vibrio cholerae non-O1/non-O139-induced diarrheal disease often develops in patients with hepatic cirrhosis and has a serious clinical course. We herein report a fatal outcome of Vibrio cholerae O67 infection in an immunocompromised MDS patient.

La epidemia de cólera en América Latina: reemergencia y morbimortalidad / The cholera epidemic in Latin America: reemergence, morbidity, and mortality

OBJETIVO: Identificar la morbilidad y la mortalidad por cólera entre distintos segmentos del período 1991-2011 en los países de América Latina. MÉTODO: Mediante el uso de fuentes de información provenientes de una búsqueda bibliográfica no sistemática de trabajos sobre epidemias del cólera, se realizó un estudio ecológico mixto dirigido a analizar series de tiempo de morbilidad, mortalidad y letalidad de estos eventos sanitarios ocurridos entre los años 1991 y 2011 en 18 países de América Latina. RESULTADOS: Durante el período 1991 y 2011 en América Latina se notificaron 1 839 037 casos de cólera, con 19 538 muertes y una letalidad de 1,06%. Los países más afectados fueron Perú entre 1991 y 2002 -con una incidencia acumulada anual máxima de 1 452,72 casos por 100 000 habitantes, pero con baja letalidad (0,72%)- y Haití entre 2010 y 2011, con una incidencia acumulada anual máxima de 3 319,13 por 100 000 habitantes y una letalidad de 1,32%. CONCLUSIONES: La epidemia de cólera ha provocado morbilidad, mortalidad y letalidad altas en algunos países de América Latina, debidas en gran medida a factores fundamentalmente socioeconómicos y climáticos. La reemergencia de esta enfermedad y la diversidad de factores relacionados con los comportamientos de sus brotes ameritan el desarrollo y el fortalecimiento de estrategias regionales de prevención y control en los países, junto con estudios de los determinantes que influyen en la emergencia y reemergencia de las enfermedades infecciosas en América Latina.

OBJECTIVE: To determine morbidity and mortality from cholera during different segments of the period 1991-2011 in the countries of Latin America. METHODS: Using information sources from a nonsystematic literature search for works on cholera epidemics, a mixed ecological study was conducted aimed at a time series analysis of morbidity, mortality, and case-fatality in cholera-related health events between 1991 and 2011 in 18 Latin American countries. RESULTS: During the period 1991-2011, 1 839 037 cases of cholera were reported in Latin America, with 19 538 deaths and a case fatality rate of 1.06%. The most affected countries were Peru between 1991 and 2002-with a maximum annual cumulative incidence of 1 452.72 cases per 100 000 population but a low case fatality rate (0.72%)-and Haiti between 2010 and 2011, with a maximum annual cumulative incidence of 3 319.13 per 100 000 population and a case fatality rate of 1.32%. CONCLUSIONS: The cholera epidemic has resulted in high morbidity, mortality, and case fatality in some Latin American countries, due largely to basically socioeconomic and climatic factors. The reemergence of this disease and the many factors related to how cholera outbreaks evolve call for the development and strengthening of regional prevention and control strategies in the countries as well as a study on the determinants that influence the emergence and reemergence of infectious diseases in Latin America.

Human epithelial cells stimulated with Vibrio cholerae produce thymic stromal lymphopoietin and promote dendritic cell-mediated inflammatory Th2 response.

Vibrio cholerae induces acute inflammatory response at intestinal epithelial surface; the underlying cellular immune mechanisms for such effects are largely unexplored. Mucosal immune response is controlled by crosstalk between the intestinal epithelial cells (ECs) and dendritic cells (DCs). An EC-derived cytokine thymic stromal lymphopoietin (TSLP) has been found a critical regulator of several human inflammatory conditions. TSLP is highly elevated in ECs stimulated with V. cholerae and its recombinant flagellin (rFlaA). V. cholerae treated human ECs produce DC-attracting chemokine MIP-3α (CCL20). Flagellin, a potent V. cholerae factor was responsible for maximum stimulation of epithelial CCL20 production and subsequent DC activation. Activated DCs express high levels of costimulatory molecules and secrete inflammatory cytokines TNF-α, IL-6 and IL-1ß. Bacteria stimulated ECs conditioned DCs to produce Th2 cell-attracting chemokines CCL17 and CCL22. TSLP and other mediators present in the V. cholerae stimulated EC-culture filtrate potently activated DCs, which subsequently primed CD4(+)T cells to differentiate into T helper type 2 (Th2) cells that produce high amounts of IL-4, IL-13 and TNF-α and low IFN-γ. TSLP-induced proinflammatory response in DCs involved the transcriptional mechanisms, MAPKs (ERK1/2, p38 and JNK) and STAT3 activation. This study suggests TSLP and other mediators released from ECs in response to V. cholerae colonization actively influence DCs in initiating inflammatory response.

Treatment of cholera-like diarrhoea with oral rehydration.

Cholera diarrhoea remains a major global health problem that has caused seven pandemics. The pathogenesis of cholera is attributable to the production of cholera toxin by the causative pathogen, Vibrio cholerae. The toxin causes increased production of cyclic adenosine monophosphate and this results in massive water and electrolyte secretion into the intestinal lumen. These changes manifest clinically as the painless defecation of voluminous stools that resemble 'rice water', leading to severe dehydration. The cornerstone in the management of cholera diarrhoea is the use of oral rehydration solutions (ORS) to replace the water and electrolytes lost as stools. The World Health Organization recommends the use of ORS of 'reduced osmolarity' for the treatment of acute non-cholera diarrhoea and the use of rice-based ORS for the management of cholera diarrhoea. Although several attempts have been made to improve ORS, studies to evaluate some of the modifications, which include the addition of amylase-resistant starch, the use of amino acids (such as glycine, alanine and glutamine) as sodium cotransporters, and zinc-supplemented ORS, are still needed.

The McKittrick-Wheelock syndrome: a case of acute renal failure due to neoplastic cholera.

The McKittrick-Wheelock syndrome is characterized by severe electrolyte and fluid depletion as a result of rectal tumor hypersecretion. Typically, a metabolic acidosis ensues. We report the case of a 58-year-old man who presented with a mixed metabolic acidosis and alkalosis. He was hyponatremic, hypokalemic, and hypochloremic, with acute renal failure on blood testing. Following fluid resuscitation, a predominant alkalemia was observed. The patient was found to be passing 1.5 L of mucous per rectum per day, containing high concentrations of sodium and potassium, similar to that observed in cholera stool. A large rectal villous adenoma was discovered on sigmoidoscopy, and definitive management was achieved by removal of the tumor. This case provides a demonstration of the ranging metabolic disturbance associated with secretory diarrhea. Other endogenous and infective causes are discussed, and mechanisms compared with the case described.

Lectin conjugates as potent, nonabsorbable CFTR inhibitors for reducing intestinal fluid secretion in cholera.

BACKGROUND & AIMS: Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to prevent intestinal fluid secretion in cholera. We previously discovered low- affinity glycine hydrazide (GlyH) CFTR inhibitors that block CFTR at its external pore. The goal of this study was to develop potent CFTR inhibitors that are minimally absorbed and washed out of the intestinal lumen for application as antisecretory agents in cholera. METHODS: GlyH analogs (malonic hydrazides, MalH) were chemically conjugated to various lectins ("MalH-lectin") and purified. CFTR inhibition potency was measured by short-circuit current analysis, mechanism of action by patch-clamp, and antidiarrheal efficacy in closed-loop and suckling mouse models. RESULTS: By lectin conjugation, we improved CFTR inhibitory potency by approximately 100-fold (to 50 nmol/L) and retarded washout. High-affinity CFTR inhibition was abolished by MalH-lectin heat denaturation, protease digestion, or competition by mannose or unconjugated lectin. Patch-clamp analysis indicated CFTR inhibition by an external pore occlusion mechanism. Fluorescently labeled MalH-lectin remained membrane bound for >6 hours after washout, whereas washout occurred in a few minutes without the lectin. MalH-ConA and MalH-wheat (IC50 50-100 pmol) blocked cholera toxin-induced intestinal fluid secretion in closed intestinal loops in mice and greatly reduced mortality in a suckling mouse model of cholera. CONCLUSIONS: The high potency of MalH-lectin conjugates results from "anchoring" the CFTR-blocking MalH to cell surface carbohydrates by the lectin. The high-affinity, slow washout, and external site of action of the MalH-lectin conjugates support their further development as antisecretory drugs for enterotoxin-mediated secretory diarrheas.

Luminally active, nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera.

Enterotoxin-mediated secretory diarrheas such as cholera involve chloride secretion by enterocytes into the intestinal lumen by the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. We previously identified glycine hydrazide CFTR blockers that by electrophysiological studies appeared to block the CFTR anion pore at its lumen-facing surface. Here, we synthesize highly water-soluble, nonabsorbable malondihydrazides by coupling 2,4-disulfobenzaldehyde, 4-sulfophenylisothiocyante, and polyethylene glycol (PEG) moieties to 2-naphthalenylamino-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] propanedioic acid dihydrazide, and aminoacethydrazides by coupling PEG to [(N-2-naphthalenyl)-2-(2-hydroxyethyl)]-glycine-2-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] hydrazide. Compounds rapidly, fully and reversibly blocked CFTR-mediated chloride current with Ki of 2-8 microM when added to the apical surface of epithelial cell monolayers. Compounds did not pass across Caco-2 monolayers, and were absorbed by <2%/hr in mouse intestine. Luminally added compounds blocked by >90% cholera toxin-induced fluid secretion in mouse intestinal loops, without inhibiting intestinal fluid absorption. These orally administered, nonabsorbable, nontoxic CFTR inhibitors may reduce intestinal fluid losses in cholera.

Helicobacter pylori-associated chronic atrophic gastritis involving the gastric body and severe disease by Vibrio cholerae.

Evidence has associated chronic infection by Helicobacter pylori with chronic gastritis, low gastric acid production and an increased risk of life-threatening cholera. However, the relationship of specific patterns of histological damage in the gastric mucosa associated with H. pylori infection and the occurrence of cholera has not been described. The purpose of this study was to compare the gastric pH and histopathological findings in gastric biopsies taken from patients with severe diarrhoeal disease due to Vibrio cholerae with those taken from a control (cholera-negative) population. Thirty-five H. pylori-positive patients who had severe dehydration from culture-confirmed cholera (cases) and 40 patients with H. pylori but with no history of cholera (controls) were recruited. Gastric pH was measured and multiple biopsies were taken from the gastric antrum and body for histopathological examination. The results revealed that patients with severe cholera had a significantly higher prevalence of hypochlorhydria at endoscopy compared with controls. Furthermore, cases had significantly more chronic atrophic gastritis (45.7% vs. 12.5%; P=0.002) and intestinal metaplasia (37.1% vs. 2.5%; P<0.01) in the gastric body than controls. Our findings suggest that the nature and location of these gastric lesions may predispose a subset of H. pylori-infected individuals to severe disease by V. cholerae.

Splenic abscess with Vibrio cholerae masking pancreatic cancer.

A 77-year-old man presented to our hospital with a clinical scenario suspicious for endocarditis with septic emboli to the lungs and splenic abscess. Vibrio cholerae was isolated from purulent material aspirated from the abscess. Medical therapy and percutaneous drainage of the abscess were unsuccessful. The patient underwent splenectomy and distal pancreatectomy revealing a pancreatic tail carcinoma involving the spleen and colon. The patient later expired secondary to metastatic disease. This case represents the first isolation of V. cholerae from a splenic abscess but also illustrates that although newer imaging technologies have made the diagnosis of splenic abscess easier, the true etiology of the abscess may remain elusive.

Vibrio cholerae non-O1 facial cellulitis in a North Queensland, Australian child.

Vibrio cholerae is an uncommon cause of cellulitis in Australia. Most reported cases worldwide have involved marine or brackish water contact. A recognized risk factor for acquiring this infection is chronic liver disease secondary to hepatitis B. We describe a case of extensive facial cellulitis caused by Vibrio cholerae non-O1, non-0139, in an 11-year-old indigenous girl from North Queensland, Australia, who was hepatitis B surface antigen-negative. Treatment consisted of extensive debridement, antibiotics, hyperbaric oxygen and facial reconstructive surgery. Early microbiologic diagnosis and a combined therapeutic approach are important in the management of this condition.