Endoscopic full-thickness resection using a clip non-exposed method for gastrointestinal tract lesions: a meta-analysis.

Background and study aims Endoscopic full-thickness resection (EFTR) allows for treatment of epithelial and sub-epithelial lesions (SELs) unsuitable to conventional resection techniques. This meta-analysis aimed to assess the efficacy and safety of clip-assisted method for non-exposed EFTR using FTRD or over-the-scope clip of gastrointestinal tumors. Methods A comprehensive literature search was performed. The primary outcome of interest was the rate of histologic complete resection (R0). Secondary outcomes of interest were the rate of enbloc resection, FTR, adverse events, and post-EFTR surgery. Random-effects model was used to calculate pooled estimates and generate forest plots. Results Eighteen studies with 730 patients and 733 lesions were included in the analyses. Indications for EFTR were difficult/residual colorectal adenoma, adenoma at a diverticulum or appendiceal orifice and early cancer (n = 634), colorectal SELs (n = 42), and upper gastrointestinal lesions (n = 51), other colonic lesions (n = 6). Median size of lesions was 13.5 mm. There were 22 failed EFTR attempts. Pooled overall R0 resection rate was 82 % (95 % CI: 75, 89). The pooled overall FTR rate was 83 % (95 % CI: 77, 89). The pooled overall enbloc resection rate was 95 (95 % CI: 92, 96). The pooled estimates for perforation and bleeding were < 0.1 % and 2 %, respectively. Following EFTR, a total of 110 patients underwent surgery for any reason [pooled rate 7 % (95 % 2, 14). The pooled rates for post-EFTR surgery due to invasive cancer, for non-curative endoscopic resection and for adverse events were 4 %, < 0.1 % and < 0.1 %, respectively. No mortality related to EFTR was noted. Conclusions EFTR appears to be safe and effective for gastrointestinal lesions that are not amenable to conventional endoscopic resection. This technique should be considered as an alternative to surgery in selected cases.

Analysis of mite allergic patients in a diverse territory by improved diagnostic tools.

BACKGROUND: There are few studies comparing the sensitization with mite allergens from different mite species which could potentially be the cause of allergy. OBJECTIVE: To improve the diagnosis of mite allergic patients from a diverse territory in which D. pteronyssinus/D. farinae mites together with storage mites could be present in the environment. METHODS: Four hundred and seventy-seven patients (both children and adults) from different regions, covering the main mite prevalent areas of Spain, were recruited. sIgE to eight allergens was measured together with SPT to whole mite extracts, level of mite allergen exposure, and specific IgG(4) . BAT and CAST was performed in a subgroup of patients. RESULTS: D. pteronyssinus and L. destructor were more prevalent in Atlantic areas, whereas D. farinae predominate in Mediterranean areas. About 90% of patients were sensitized to group 1 and/or group 2 allergens. Group 2 was the most prevalent, and the IgE response/intensity of sensitization in BAT was higher. sIgE to Der p 2/Der f 2 was almost fully cross-reactive, but no cross-reactivity was detected with Lep d 2. Group 1 allergens were also cross-reactive, but in some patients a species-specific response was observed. sIgE to Lep d 2 was associated with SPT results to storage mites. Sensitization to Der p 1 was more frequent in children, whereas Lep d 2 sensitization was more frequent in adults. A higher ratio IgE/IgG(4) to Der p 2 was associated with the presence of allergic asthma. CONCLUSION: An improved diagnosis algorithm has been established. Group 2 allergens seem to have a leading role in mite allergy, but as group 1 sensitization could be species-specific in some patients and its prevalence is higher in children, an adequate balance on major mite species and major allergens must be consider in the design of mite allergy vaccines.

Irritant-induced asthma: clinical and functional aspects.

We report on three patients who experienced persistent asthma symptoms after repetitive irritant exposure which took place over a period from several days to months. Airway inflammation was assessed by induction of sputum and functional follow-up information was obtained from serial lung function tests. All patients had bronchial hyperresponsiveness to methacholine at the time of diagnosis. However, induced sputum samples did not show increased differential count of eosinophils. Treatment with inhaled corticosteroids was started in all of the patients and two of them were removed from work. In the two patients who left the workplace, methacholine inhalation test became negative when symptoms disappeared, whereas the patient who continued working had persistent asthma symptoms and a deterioration of bronchial hyperresponsiveness.

Retroviral vector-mediated transfer of the galactocerebrosidase (GALC) cDNA leads to overexpression and transfer of GALC activity to neighboring cells.

Galactocerebrosidase (GALC) is responsible for the lysosomal catabolism of certain galactolipids, including galactosylceramide and psychosine. Patients with GALC deficiency have an autosomal recessive disorder known as globoid cell leukodystrophy (GLD) or Krabbe disease. Storage of undegraded glycolipids results in defective myelin and the characteristic globoid cells observed on pathological examination of the central and peripheral nervous systems. Most patients have the infantile form of GLD, although older individuals are also diagnosed. Recently the human, mouse, and canine GALC genes were cloned, and mutations causing GLD have been identified. We now describe the construction of a vector containing human GALC cDNA (MFG-GALC), and the transduction of cultured skin fibroblasts from molecularly characterized Krabbe disease patients, as well as rat brain astrocytes and human CD34(+) hematopoietic cells, using retrovirus produced by the psi-CRIP amphotropic packaging cell line. The transduced fibroblasts showed extremely high GALC activity (up to 20,000 times pretreatment levels, about 100 times normal). GALC was secreted into the media and was taken up by untransduced fibroblasts from the same or a different patient. Mannose-6-phosphate receptor-mediated uptake was only partially responsible for the efficient transfer of GALC to neighboring cells. Additional studies confirmed the presence of normal GALC cDNA and mRNA in the transduced cells. The GALC produced by the transduced cells and donated to neighboring untransduced cells was localized to lysosomes as demonstrated by the normal metabolism of [14C]stearic acid-labeled galactosylceramide produced from endocytosed [14C]sulfatide.

Responses of immunoreactive ACTH and bioactive ACTH to large hemorrhage and resuscitation in conscious dogs.

We studied the effect of fluid resuscitation on immunoreactive adrenocorticotropic hormone (irACTH) and bioactive ACTH (bioACTH) after hemorrhage in conscious dogs. Animals (n = 7) were bled 30% (approximately 25 ml/kg) over 3 min and 30 min later were either resuscitated [43.3 ml/kg 0.9% NaCl (1.8 times hemorrhage volume) over 10 min] or not. Blood was reinfused after 210 min. Animals had both treatments (> 4 days apart). irACTH, bioACTH, cortisol, angiotensin II, and aldosterone increased rapidly after hemorrhage. Resuscitation increased blood volume and cardiac output to resting values, but arterial hypotension persisted. bioACTH and irACTH decreased 40-90 min after hemorrhage in both groups, but each decreased more rapidly after resuscitation. The elimination half-life of bioACTH was shorter than that of irACTH, but neither was affected by resuscitation. The ratio of bioACTH to irACTH followed the same pattern with or without resuscitation. Angiotensin II and aldosterone remained increased without resuscitation but decreased promptly after resuscitation. In conclusion, 1) saline infusion at 1.8 x hemorrhage volume provides effective cardiovascular resuscitation, with resolution of hormonal responses to hemorrhage; 2) although ACTH responses resolved with or without resuscitation, resuscitation produced more rapid resolution without changing the parameters of ACTH elimination; 3) the dynamics of the resolution of the ACTH response to hemorrhage are similar whether induced by stimulus removal or feedback inhibition.

Metachromatic leukodystrophy among southern Alaskan Eskimos: molecular and genetic studies.

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder resulting from the inability to metabolize sulphatide, an important component of myelin. Although there is significant clinical variability between patients, most have the late-infantile form. It is one of the most common lysosomal disorders involving mental deterioration and is found throughout the world. The great majority of the cases have a deficiency of arylsulphatase A activity. Accurate diagnosis of MLD is complicated by the presence of so-called pseudodeficiency alleles and the need to receive specimens for biochemical testing within 24-48 h of collection. We report the identification of the mutation (a g-to-a transition in the first nucleotide of intron 4) in the arylsulphatase A gene causing late-infantile MLD among the Eskimo population of southern Alaska. As all patients and family members from living and deceased patients had the same mutation, a mutation-based test was developed to identify patients and carriers that can be done on dried blood spots sent via regular mail service. A possible genetic link between this population and the Navajo Indians of the southwestern United States is proposed.

Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy.

Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. GALC is responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. We describe the molecular cloning of human GALC cDNA and its expression in COS-1 cells. Degenerate PCR primers, derived from N-terminal amino acid sequence from the 51 kDa band from human brain, were used to amplify cat testes RNA, and the resulting product was used to screen human testes and brain libraries. Two overlapping clones contained the total protein coding region, while additional clones and PCR amplification were needed to obtain the complete 3' end of the cDNA. The 3795 bp obtained include 47 bp 5' to the initiation start site, 2007 bp of open reading frame (coding for 669 amino acids), and 1741 bp of 3' untranslated sequence. Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells. The isolation of this clone will permit investigations into the causes for GALC deficiency in humans and available animal models, development of more accurate tests for patient and carrier identification, and evaluation of methods for effectively treating GALC deficiency, initially using the animal models.

Mutational analysis in a patient with a variant form of Gaucher disease caused by SAP-2 deficiency.

It is now clear that the lysosomal hydrolysis of sphingolipids requires both lysosomal enzymes and so-called sphingolipid activator proteins (SAPs). One gene, called prosaposin, codes for a precursor protein that is proteolytically cut into four putative SAPs. These four SAPs, of about 80 amino acids, share some structural features but differ somewhat in their specificity. Domain 3 of prosaposin mRNA contains the coding region for SAP-2, an activator of glucocerebrosidase. While most patients with Gaucher disease store glucosylceramide due to defects in glucocerebrosidase, a few patients store this lipid in the presence of normal enzyme levels. In this paper we describe the identification of a point mutation in domain 3 of a patient who died with this variant form of Gaucher disease. Polymerase chain reaction amplification was performed in the small amount of genomic DNA available using primers generated from the intronic sequence surrounding domain 3. The patient was found to have a T-to-G substitution at position 1144 (counting from the A of ATG initiation codon) in half of the M13 recombinant clones. This changes the codon for cysteine382 to glycine. His father and unaffected brother also had this mutation, but his mother did not. She was found to have half of the normal amount of mRNA for prosaposin in her cultured skin fibroblasts. Therefore, this child inherited a point mutation in domain 3 from his father and a deficiency of all four SAPs coded for by prosaposin from his mother.

Saline resuscitation after fixed-volume hemorrhage. Role of resuscitation volume and rate of infusion.

The authors have reported previously that small-volume resuscitation (1.8 x bled volume) with 0.9% NaCl restores blood volume and attenuates hormonal responses after large hemorrhage without correction of arterial hypotension. The authors studied the role of rate of infusion in this observation in chronically prepared dogs (aortic flow probe, right atrial pressure and volume, and arterial catheters) after 30% hemorrhage (24.1 +/- 0.4 mL/kg). After 30 minutes, subjects were observed either without treatment (no resuscitation) or with infusion of 43 mL/kg 0.9% NaCl over 3 hours by one of three protocols: (1) impulse infusion over 10 minutes, (2) variable rate infusion, bolus with tapering infusion, or (3) constant rate infusion. Significant improvement in cardiac output and in blood volume and significant decreases of vasopressin and arterial catecholamines were observed in all fluid-treated groups. This benefit was relatively independent of rate of infusion, although impulse infusion produced greater early improvement, which dissipated with time, and constant rate infusion produced better late results. In none of the fluid-treated groups were these improvements reflected in improved mean arterial pressure compared with the no resuscitation group. The authors conclude that small-volume, slow-rate saline infusion produces physiologic benefits that cannot be assessed by easily measured clinical parameters. Thus, early resuscitation after trauma could aid patients even if arterial pressure is unchanged. This benefit might be even greater in patients with uncontrolled bleeding because arterial pressure, and hence bleeding, may not be increased by resuscitation of this type. A reassessment of the value of prehospital fluid resuscitation in the injured patient is warranted.

Comparison of carotid baroreflex control of plasma AVP concentration in conscious and anesthetized dogs.

We compared carotid sinus baroreflex control of endogenous plasma arginine vasopressin (AVP) in chronically prepared conscious and acutely prepared anesthetized dogs. The carotid sinuses of both conscious and pentobarbital-anesthetized dogs were isolated bilaterally and perfused at constant pressures. Carotid sinus pressure (CSP) was changed between 200 and 50 mmHg in 25-mmHg steps in intact conscious and anesthetized dogs. Similar runs were repeated after vagotomy. Mean arterial pressure (MAP) and heart rate (HR) were monitored. At each interval of CSP, blood was withdrawn for AVP analysis by radioimmunoassay. MAP responses to changes in CSP were not different in the four experimental groups. Both anesthesia and vagotomy increased the HR responses to changes in CSP. With vagi intact, AVP increased at high CSP in conscious but not in anesthetized dogs. After vagotomy, low CSP led to an increase in plasma AVP that did not differ between conscious and anesthetized dogs. The results suggest that the release of AVP is modulated by the action of the carotid baroreflex as a normal component of an integrated efferent response. The response is similar in conscious and pentobarbital-anesthetized dogs and is normally buffered by reflexes with vagal afferents.

Interaction of sodium and volume in fluid resuscitation after hemorrhage.

Some measures of the efficacy of fluid resuscitation after hemorrhage are blood volume restitution (BVR) and attenuation of the neuroendocrine response. We compared the effectiveness of resuscitation with 0.9% NaCl and 3.0% NaCl in chronically prepared awake dogs after 30% hemorrhage. Each dog was bled on four occasions and resuscitated by four protocols: 1) full resuscitation (infusion to return and maintain mean arterial pressure (MAP) at control +/- 10 mm Hg) with 3.0% NaCl (HS); 2) full resuscitation with 0.9% NaCl (NS); 3) under-resuscitation with a volume of 0.9% NaCl equal to the subject's previous 3.0% NaCl requirement (SV); and 4) no fluid therapy (NR). Approximately three times more volume was needed to restore MAP with NS vs. HS, and thus the amount of Na administered was not different in these groups. Net volume balance was positive in the NS and SV groups but negative in the HS group due to marked saline diuresis. Net Na balance was positive in all three fluid-treated groups, but significantly higher in the HS group (p less than 0.01). MAP remained below baseline in the SV and NR groups (p less than 0.05). BVR exceeded 100% in NS and HS early in resuscitation, but BVR was not sustained in the HS group. Total plasma protein increased in all three fluid treated groups. Responses of all hormones were completely attenuated in the NS group. ACTH, cortisol, and AVP responses were promptly attenuated in the HS group, but remained greater than control. In the SV group, all hormone levels except renin returned to control values, but more slowly than the other groups. ACTH and cortisol correlated best with BVR; AVP, PRA, and aldosterone correlated with MAP restoration. In summary, resuscitation with either HS or NS can achieve similar MAP restoration. Hypertonic saline produces a more rapid increase in BVR and MAP, but the BVR improvement is transient. Resuscitation with HS incurs an intracellular water debt which is aggravated by a saline diuresis. Hormonal attenuation is linked either to BVR (ACTH, cortisol) or to MAP restoration (renin, AVP). Thus the optimal resuscitation regimen may consist of initial infusion of hypertonic saline followed by sufficient hypotonic solution to restore interstitial fluid volume and normal cellular hydration.

The language of altered states.

To compare the subjective experience of different forms of altered states of consciousness, computerized content analysis was applied to 66 autobiographical accounts of schizophrenia, hallucinogenic drug states, or mystical ecstasy and to 28 autobiographical control accounts of important personal experiences. The patterns of lexical choice used by the four groups were significantly different in word frequencies from 49 of 83 lexical categories measured. When data from the 13 most statistically significant categories were used in discriminant and classification analyses, 84% of the samples were correctly identified by their word frequencies. These findings suggest that the subjective experiences of schizophrenia, hallucinogenic drug-induced states, and mystical ecstasy are more different from one another than alike.