Clinical outcome of transfemoral embolisation in patients with arteriovenous malformations of the liver in hereditary haemorrhagic telangiectasia (Weber-Rendu-Osler disease)

Background—Arteriovenous malformations of theliver in Osler's disease may present as high output cardiac failure. Afew case reports suggested that treatment with arterial embolisationmay have beneficial effects in such patients.
Aims—To investigate the efficacy and safety ofthis treatment modality in a prospective pilot study.
Patients and methods—Four women and one man (aged39-59 years) with the dominant hepatic manifestation of Osler'sdisease presented with symptoms of cardiac failure and elevated cardiac output. Arteriovenous malformations were treated in three to five sessions with arterial embolisation using coils. The outcome was analysed by measurement of cardiac output and scoring of clinical symptoms.
Results—Embolisation was technically feasible inall patients and adequate occlusion of vascular malformations wasachieved in four patients. After completion of therapy symptomsimproved in four patients, while one patient suffered from abdominalpain due to cholangitis. One patient died seven months after theembolisation treatment from variceal bleeding. Mean cardiac outputsignificantly decreased from 14.2 (range 12-17.3) l/min to 8 (range5.9-10.6) l/min (p=0.043). After a median follow up of 23 months(range 7-50 months), three of five patients had a long lastingimprovement of clinical symptoms and cardiac function.
Conclusions—This first treatment series ofpatients with dominant hepatic involvement in Osler's diseaseindicates that arterial embolisation may prevent cardiac failure bysignificantly lowering cardiac output.

Keywords:hereditary haemorrhagic telangiectasia; Weber-Rendu-Osler disease; hepatic vascular malformation; cardiacfailure; embolisation therapy

     

Synchrones Auftreten dreier seltener Tumoren

A 70-year-old woman presented with nasal obstruction and pain projecting onto the left cheek. The face seemed asymmetric including exophthalmus on the right side. Nasal endoscopic inspection revealed a sarcomatous tumor located on the middle turbinate. The CT showed that the tumor filled the left maxillary sinus completely and had eroded the maxillary bone. In addition, a round, sharply defined intraorbital neoplasm on the right side was identified in the contrast-enhanced MRI. Histological examination of the extirpated intraorbital tumour showed a neurilemmoma. A tissue biopsy of the intranasal tumour falsely suggested an intestinal adenocarcinoma. Multiple neoplasms suspicious of disseminated lung metastases were detected in the CT of the thorax. One round lesion removed by thoracoscopy revealed a carcinoid. The intranasal tumour was excised completely and the histology proved beyond doubt an inverted papilloma.     

The mini-rhino-conjunctivitis quality of life (qol) questionnaire (mrqlq) — self administered

Objective Our aim was to administer the MRQLQ Questionnaire in Indian adults with allergic rhino-conjunctivitis (ARc). Criteria for inclusion in the study Adults with chronic ARc, with sufficiently troublesome current symptoms, attending The Allergy Clinic of The Hinduja Hospital, Mumbai, during March–August 2006 were selected. Results The five highest PS were seen with sneezing 290, irritation 238, running nose 228, stuffy nose 220, anxiety 203 and interrupted working 203. The 5 lowest PS were seen with disturbed sleep 83, dry throat 98, affected walking for 1/2 kilometre 98, do not sleep deeply 103 and phlegm 105. Discussion The five highest PS were due to symptoms of rhinitis, general irritation, anxiety & interruption of work. Thus rhinitis itself affects QOL. The 5 least PS were mainly sleep-related. Conclusion We have applied the MRQLQ on Indian patients with ARc. We could obtain a product score for every item in it, on the basis of which we could classify the degree of its effect on his QOL. PS was highest in rhinitis-related symptoms. 2 Emotions related and 1 Role limitation item gave moderate PS, while all PS in eye related, Physical functioning, Social functioning, Sleep-related & Other Symptoms items were in the mild range. Larger data sample is needed to validate and show its discriminatory power.     

Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells

Abstract:  Cholesterol is important for membrane stability and is the key substrate for the synthesis of steroid hormones and vitamin D. Furthermore, it is a major component of the lipid barrier in the stratum corneum of the human epidermis. Considering that steroid hormone synthesis is taking place in epidermal melanocytes, we tested whether downstream oestrogen receptor/cAMP signalling via MITF/tyrosine hydroxylase/tyrosinase/pigmentation could be possibly modulated by cholesterol. For this purpose, we utilized human primary melanocyte cell cultures and human melanoma cells with different pigmentation capacity applying immunofluorescence, RT-PCR, Western blotting and determination of melanin content. Our in situ and in vitro results demonstrated that melanocytes can synthesize cholesterol via HMG-CoA reductase and transport cholesterol via LDL/Apo-B100/LDLR. Moreover, we show that cholesterol increases melanogenesis in these cells and in human melanoma cells of intermediate pigmentation (FM55) in a time- and dose-dependent manner. Cellular cholesterol levels in melanoma cells with different pigmentation patterns, epidermal melanocytes and keratinocytes do not differ except in the amelanotic (FM3) melanoma cell line. This result is in agreement with decreasing cholesterol content versus increasing pigmentation in melanosomes. Cholesterol induces cAMP in a biphasic manner i.e. after 30 min and later after 6 and 24 h, meanwhile protein expression of oestrogen receptor β, CREB, MITF, tyrosine hydroxylase and tyrosinase is induced after 72 h. Taken together, we show that human epidermal melanocytes have the capacity of cholesterol signalling via LDL/Apo-B100/LDL receptor and that cholesterol under in vitro conditions increases melanogenesis.     

Molecular Authentication of Medicinal Plant, <Emphasis Type="Italic">Swertia</Emphasis><Emphasis Type="Italic">chirayita</Emphasis> and its Adulterant Species

Swertia is ethno-medicinally an important genus belonging to family Gentianaceae. Swertia chirayita is used as imperative medicinal plant in Indian system of medicine. However, this species has been frequently adulterated due to its high demand and scarcity. Authentication of this species was needed to protect consumers and conservation measures and to find out the alternative source. Deoxyribose nucleic acid (DNA) extracted from fifteen samples of six species belonging to different localities, were used as templates. Four candidate barcodes were amplified by polymerase chain reaction and sequence analysis was executed by Z-Big Dye Terminator Cycle Sequencing v.3. Sequenced products were analyzed on automated applied biosystems 3730XI analyzer. Identification was performed by using molecular evolutionary genetics analysis 5 software (version 5.1). The amplification efficiency of all DNA barcodes [megakaryocyte-associated tyrosine kinase (matK), ribulose-bisphosphate carboxylase (rbcL), photosystem II protein D1- stuctural RNA- His tRNA (psbA-trnH) and internal transcribed spacer region (ITS)] was 100 %. Here, the highest interspecific divergence provided by ITS is 11.87 % and intraspecific by psbA-trnH being 10.22 % as compared to matK (5.04 %) and rbcL (0.99 %). ITS region proves robust molecular marker for differing the S. chirayita from its related adulterant species. All barcoding regions indicate that S. chirayita and S. minor both are more closely related than other Swertia species. Findings showed that DNA barcoding is an efficient tool for identification and authentication of S. chirayita. Use of S. minor as substitute to S. chirayita can be advocated.     

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α₁-adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α_1A/B-ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α_1A/B-AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α_1A/B-AR and CXCR4, and inhibited Ca²⁺ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α₁-AR activation. CXCR4 silencing reduced α_1A/B-AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca²⁺ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC₅₀ of the phenylephrine-induced blood pressure response three- to fourfold. These observations suggest that disruption of the quaternary structure of α_1A/B-AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit α₁-AR–mediated function in VSMC and that activation of CXCR4 enhances the potency of α₁-AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating α₁-AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the α_1A/B-AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure.Chemokine (C-X-C motif) receptor 4 (CXCR4) is a G protein-coupled receptor (GPCR) that is essential during development. Animals lacking CXCR4 are not viable and demonstrate defects of the hematopoietic and cardiovascular system (1). After birth, CXCR4 is expressed in many tissues, including the heart and vasculature, and fulfills multiple functions in the immune system, such as regulation of leukocyte trafficking, stem cell mobilization, and homing (2, 3). Moreover, CXCR4 is involved in various disease processes, such as HIV infection, cancer metastasis, and tissue repair (3–5).In addition to these established functions, recent observations suggest that CXCR4 also contributes to the regulation of hemodynamics and blood pressure. Treatment with the CXCR4 antagonists AMD3100 and AMD3465 reduced blood pressure in experimental models of pulmonary arterial and systemic hypertension (6, 7). We have shown previously that AMD3100 reduces hemodynamic stability and blood pressure during the cardiovascular stress response to traumatic and hemorrhagic shock, whereas selective activation of CXCR4 with the noncognate agonist ubiquitin improves hemodynamic stability and increases systemic blood pressure after traumatic, hemorrhagic, and endotoxic shock (8–13). Because in vivo pharmacological targeting of CXCR4 did not affect myocardial function, these findings suggested that effects of CXCR4 on hemodynamics and blood pressure are mediated via modulation of vascular function (9). Accordingly, we observed that CXCR4 activation enhances and sensitizes vasoconstriction of isolated mesenteric arteries and veins in response to α₁-adrenergic receptor (AR) activation with phenylephrine (PE) (9). As these effects were independent of the vascular endothelium, interactions between CXCR4 and α₁-AR in vascular smooth muscle likely constitute the physiological basis for these observations (9). The molecular mechanisms underlying interactions between CXCR4 and α₁-AR in vascular smooth muscle, however, remain unknown.Crosstalk between GPCRs is a widely recognized principle that expands the physiological repertoire of GPCR-mediated signaling events and functions (14–19). Receptor crosstalk can be attributed to a variety of molecular mechanisms, including receptor hetero-oligomerization (14–23). The formation of homo- and/or hetero-oligomeric complexes among GPCRs is thought to be important for many aspects of GPCR function (22–24).CXCR4 has been shown to associate with multiple chemokine receptors in various expression systems (3, 25–28). ARs are also known to be able to form heteromeric receptor complexes (29–35), and recent evidence suggests that AR may also be able to form heteromeric complexes with chemokine receptors (36–38). Thus, we studied whether α₁-AR and CXCR4 may interact on the cell surface of vascular smooth muscle cells through the formation of heteromeric receptor complexes.Here, we provide evidence that heteromeric receptor complexes between α_1A-AR and CXCR4 and between α_1B-AR and CXCR4 are constitutively expressed in rat and human vascular smooth muscle cells (VSMC). We show that disruption of the quaternary structure of the heteromeric receptor complex by targeting transmembrane helix (TM) 2 of CXCR4 and depletion of heteromeric receptor complexes by CXCR4 knockdown inhibit α₁-AR agonist-induced key signaling events and contraction of VSMC. Furthermore, we show that treatment with CXCR4 agonists increases the potency of the α₁-AR agonist PE to increase blood pressure in vivo. Our observations suggest that α₁-AR function in VSMC is controlled through the formation of heteromeric α_1A/B-AR:CXCR4 complexes.     

Opening of Psychiatric Observation Unit Eases Boarding Crisis

Objectives

The objective of this study was to evaluate the effect of a psychiatric observation unit in reducing emergency department (ED) boarding and length of stay (LOS) for patients presenting with primary psychiatric chief complaints. A secondary outcome was to determine the effect of a psychiatric observation unit on inpatient psychiatric bed utilization.

Methods

This study was a before‐and‐after analysis conducted in a 1,541‐bed tertiary care academic medical center including an adult ED with annual census over 90,000 between February 2013 and July 2014. All adult patients (age > 17 years) requiring evaluation by the acute psychiatry service in the crisis intervention unit (CIU) within the ED were included. Patients who left without being seen, left against medical advice, or were dispositioned to the pediatric hospital, hospice, or court/law enforcement were excluded. In December 2013, a 12‐bed locked psychiatric observation unit was opened that included dedicated behavioral health staff and was intended for psychiatric patients requiring up to 48 hours of care. The primary outcomes were ED LOS, CIU LOS, and total LOS. Secondary outcomes included the hold rate defined as the proportion of acute psychiatry patients requiring subsequent observation or inpatient admission and the inpatient psychiatric admission rate. For the primary analysis we constructed ARIMA regression models that account for secular changes in the primary outcomes. We conducted two sensitivity analyses, first replicating the primary analysis after excluding patients with concurrent acute intoxication and second by comparing the 3‐month period postintervention to the identical 3‐month period of the prior year to account for seasonality.

Results

A total of 3,501 patients were included before intervention and 3,798 after intervention. The median ED LOS for the preintervention period was 155 minutes (interquartile range [IQR] = 19–346 minutes), lower than the median ED LOS for the postintervention period of 35 minutes (IQR = 9–209 minutes, p < 0.0001). Similar reductions were observed in CIU LOS (865 minutes vs. 379 minutes, p < 0.0001) and total LOS (1,112 minutes vs. 920 minutes, p = 0.003). The psychiatric hold rate was statistically higher after intervention (before = 42%, after = 50%, p < 0.0001), however, coupled with a statistically lower psychiatric admission rate (before = 42%, after = 25%, p < 0.0001).

Conclusions

Creation of an acute psychiatric observation improves ED and acute psychiatric service throughput while supporting the efficient allocation of scare inpatient psychiatric beds. This novel approach demonstrates the promise of extending successful observation care models from medical to psychiatric illness with the potential to improve the value of acute psychiatric care while minimizing the harms of ED crowding.

     

Psychotherapy improves compliance with tuberculosis treatment

BACKGROUND: Low treatment completion rate in tuberculosis (TB) patients is a major concern. Physicians have always been striving for better treatment adherence in such patients. The present study is one such attempt in this direction. OBJECTIVES: The study was aimed to evaluate the role of behavior modification by psychotherapy in improving compliance with short-course anti-TB chemotherapy in India. METHODS: It was a prospective controlled trial involving patients with confirmed pulmonary and extrapulmonary TB enrolled in the National Tuberculosis Program. The intervention group underwent pretreatment psychological assessment followed by regular psychotherapy sessions. RESULTS: The intervention group had a demographic profile comparable to that of the control group. The patients were mostly from low- and middle-income backgrounds from urban and semi-urban areas. They consistently showed poor knowledge about the nature of the disease, low motivation, and had considerable apprehensions. Following the sessions, the intervention group showed improved compliance compared with the control group, reflected in significantly higher treatment completion and cure rates. CONCLUSIONS: The study suggests that psychological intervention is effective in improving compliance with anti-TB treatment, and may reduce the incidence of treatment failure, relapse and drug resistance.