Evaluation and Management Strategies for GI Involvement with Amyloidosis.

Amyloidosis is a heterogeneous disease that can cause a wide array of nonspecific symptoms when the gastrointestinal (GI) tract is involved, including weight loss, early satiety, change in bowel habits with diarrhea, constipation, or alternating bowel pattern. Endoscopy with biopsy for Congo red staining establishes the diagnosis and fibril subtyping helps to guide targeted treatment options. Light chain amyloidosis is the most frequent subtype found throughout the GI tract. Transthyretin amyloidosis is most likely to be found on rectal biopsy. Management of the symptoms of GI tract involvement with amyloidosis relate to addressing the underlying symptom complex that is produced and generally abstracted from the management of severe forms of functional GI disorders. Attention to improving symptom management and nutrition status can improve quality of life in these patients.

Unexpected High Prevalence of Lymphocytic Infiltrates in Myenteric Ganglions in Intestinal Inertia.

Intestinal inertia is a severe form of gut dysmotility that may require surgical resection. Loss of myenteric ganglion cells has been proposed as a possible etiology. Preclinical models have also suggested that virus infection-associated ganglionitis may be an alternative pathogenic factor. We determined to the extent intestinal inertia is associated with the lack of myenteric ganglion cells or ganglionitis using resection specimens from 27 intestinal inertia and 28 colon cancer patients. A hot spot approach with 5 HPFs was used for quantifying inflammatory cells. CD3, CD8, and CD20 immunohistochemistry was used to quantify T and B lymphocytes, along with subtyping the T-lymphocyte population by CD8. None of the intestinal inertia nor control cases showed the absence of myenteric ganglion cells. A total of 15 (55.6%) of the intestinal inertia cases showed inflammatory cell infiltration in the myenteric ganglion cells, compared with only 1 of 28 (3.6%) control cases (P<0.0001 by Fisher exact test). The inertia cases with inflammatory infiltrates were all associated predominantly with lymphocytes, including 3 cases (11.1%) with concurrent eosinophil infiltration, and 1 case (3.7%) with concurrent neutrophil infiltration. Furthermore, all 15 inertia cases with myenteric lymphocytic ganglionitis were associated with T lymphocytes (100%), including 1 case with a subset of concurrent B lymphocytes. The average CD3 count was 3.8 cells/HPF. CD8 immunohistochemical stain showed positive staining in 12 of the 15 cases (80%) with CD8-positive cells ranging from 1 to 8/HPF. In contrast, the only control case with lymphocytic ganglionitis showed mixed B and T lymphocytes and eosinophils. The high prevalence of T-lymphocyte infiltration in the myenteric ganglion in intestinal inertia cases suggests a possible pathogenic role.

Pancreatic and Intestinal Function Post Roux-en-Y Gastric Bypass Surgery for Obesity.

OBJECTIVES: Despite the fact that the most effective treatment for morbid obesity today is gastric bypass surgery, some patients develop life-threatening nutritional complications associated with their weight loss. METHODS: Here we examine the influence of the altered anatomy and digestive physiology on pancreatic secretion and fat absorption. Thirteen post Roux-en-Y gastric bypass (RYGB) patients who had lost >100 lbs in the first year following surgery and who gave variable histories of gastrointestinal (GI) dysfunction, were selected for study. Food-stimulated pancreatic enzyme secretion and GI hormone responses were measured during 2 h perfusions of the Roux limb with a standard polymeric liquid formula diet and polyethylene glycol marker, with collections of secretions from the common channel distal to the anastomosis and blood testing. Fat absorption was then measured during a 72 h balance study when a normal diet was given containing ~100 g fat/d. RESULTS: Result showed that all patients had some fat malabsorption, but eight had coefficients of fat absorption <80%, indicative of steatorrhea. This was associated with significantly lower feed-stimulated secretion rates of trypsin, amylase, and lipase, and higher plasma peptide-YY concentrations compared with healthy controls. Five steatorrhea patients were subsequently treated with low quantities of pancreatic enzyme supplements for 3 months, and then retested. The supplements were well tolerated, and fat absorption improved in four of five patients accompanied by an increase in lipase secretion, but body weight increased in only three. Postprandial breath hydrogen concentrations were elevated with some improvement following enzyme supplementation suggesting persistent bacterial overgrowth and decreased colonic fermentation. CONCLUSIONS: Our investigations revealed a wide spectrum of gastrointestinal abnormalities, including fat malabsorption, impaired food stimulated pancreatic secretion, ileal brake stimulation, and bacterial overgrowth, in patients following RYGB which could be attributed to the breakdown of the normally highly orchestrated digestive anatomy and physiology.

Peptide inhibitors of alpha-amylase based on tendamistat: development of analogues with omega-amino acids linking critical binding segments.

Peptide analogues of Tendamistat which include the most essential residues linked by novel omega-amino acids (X,Y,Z: H2N-(CH2)n-CO(2)H, where n=2-10) were designed, synthesized (Ac-Tyr(15)-X-Trp(18)-Arg(19)-Tyr(20)-Y-Thr(55)-Z-Asp(58)-Gly(59)-Tyr(60)-Ile(61)-Gly(62)-NH2), and analyzed for alpha-amylase inhibitory activity. Native dipeptide spacers sometimes were left intact at X and Z. Analogues demonstrated competitive inhibition with K(i) values ranging from 23 to 767 microM. 8-Aminooctanoic acid was the optimal linker at Y, while longer linkers were favored at the other positions.

Correlation of LUMO localization with the alpha-amylase inhibition constant in a Tendamistat-based series of linear and cyclic peptides.

The glycosidase alpha-amylase is responsible for the hydrolysis of alpha(1-->4) glycosidic linkages found in dietary starch as one means for controlling blood sugar level. The effect of alpha-amylase is detrimental, however, in the disease state diabetes mellitus, where blood glucose levels are elevated due to a biochemical defect. Inhibition of the enzyme's activity would reduce glucose absorption by the small intestine. Our objective was to develop small peptides based on essential binding elements of the natural protein inhibitor, Tendamistat. These smaller analogs may be better studied structurally and conformationally to help us understand molecular-level interactions. In addition, we have been able to correlate the activity of our compounds with the lowest unoccupied molecular orbital (LUMO) localization in energy-minimized conformations. The positive charge/LUMO of most active inhibitors is localized on the central Arg residue of the required triplet. This provides a predictive model for the design of active molecules.