Evidence of ß-Cell Dedifferentiation in Human Type 2 Diabetes.

CONTEXT: Diabetes is associated with a deficit of insulin-producing ß-cells. Animal studies show that ß-cells become dedifferentiated in diabetes, reverting to a progenitor-like stage, and partly converting to other endocrine cell types. OBJECTIVE: To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors. DESIGN: We scored dedifferentiation using markers of endocrine lineage, ß-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3. RESULTS: By these criteria, dedifferentiated cells accounted for 31.9% of ß-cells in type 2 diabetics vs 8.7% in controls, and for 16.8% vs 6.5% of all endocrine cells (P < .001). The number of aldehyde dehydrogenase 1A3-positive/hormone-negative cells was 3-fold higher in diabetics compared with controls. Moreover, ß-cell-specific transcription factors were ectopically found in glucagon- and somatostatin-producing cells of diabetic subjects. CONCLUSIONS: The data support the view that pancreatic ß-cells become dedifferentiated and convert to α- and δ-"like" cells in human type 2 diabetes. The findings should prompt a reassessment of goals in the prevention and treatment of ß-cell dysfunction.

Kidneys at higher risk of discard: expanding the role of dual kidney transplantation.

Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI)>85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80-90% and >90%). Kidneys with KDPI>90% were associated with increased odds of discard (OR=1.99, 95% CI 1.74-2.29) compared to ones with KDPI<80%. DKTs of KDPI>90% were associated with lower overall allograft failure (HR=0.74, 95% CI 0.62-0.89) and better patient survival (HR=0.79, 95% CI 0.64-0.98) compared to single ECD kidneys with KDPI>90%. Kidneys at higher risk of discard may be offered in the up-front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile.

Multivisceral ex vivo surgery for tumors involving celiac and superior mesenteric arteries.

Abdominal tumors involving both roots of the celiac and superior mesenteric artery are deemed unresectable by conventional surgical methods. We performed three cases of multivisceral ex vivo surgery involving temporary removal of the entire abdominal viscera followed by vascular reconstruction, ex vivo tumor resection and autotransplantation of excised organs. We achieved a complete tumor resection with negative margins in all cases. All patients have survived with no tumor recurrence to date at 17-, 27- and 38-month follow-up. Postoperative complications included diarrhea, sphincter of Oddi dysfunction and arterial stenosis; all responded to directed treatments. Multivisceral ex vivo surgery applying techniques of deceased donor multivisceral transplantation is feasible in achieving local control of otherwise unresectable abdominal tumors. This surgery is best suitable for locally invasive tumors unresectable because of location and vascular involvement.

When disaster strikes: death of a living organ donor.

Donor safety is of paramount importance in living donor transplantation. Yet, living donor deaths occur. We believe that problems exist in our system of live donor transplantation that can be summarized in a series of simple statements: (1) Donor mortality can never be completely eliminated; (2) Live donor risk has not been mitigated so that it is as low as possible; (3) After a donor death, systematic reviews are not routinely performed to identify correctable causes; (4) The lessons learned from any donor death are not adequately communicated to other programs and (5) The administrative mechanisms and resources are not universally available at all transplant centers to implement lessons learned. To rectify these problems, we propose the following: (1) A national living donor death task force be established with the purpose of performing systematic reviews of any donor death. (2) Findings of these reviews be disseminated to all institutions performing live donor transplants on a secure, password-protected website. (3) A no-fault donor death indemnity fund be established to provide a financial imperative for institutions to cooperate with this external peer-review. These measures will serve the best interests of the involved institutions, the transplant community, and most importantly, the patients and their families.

Additive effects of exposure to silica dust and smoking on pulmonary epithelial permeability: a radioaerosol study with technetium-99m labelled DTPA.

BACKGROUND: Increased pulmonary epithelial permeability evaluated by the rate of clearance from lung to blood of the radioaerosol solute technetium-99m labelled diethylenetriamine pentaacetate (99mTc-DTPA) has been reported in smokers and in workers exposed to silica dust. A study was carried out to determine whether there are additive effects of cigarette smoke and exposure to silica dust on clearance rates of 99mTc-DTPA in ceramic workers. METHODS: Thirty one subjects with silicosis were studied, of whom 18 smoked cigarettes and 13 were non-smokers. They had similar histories of exposure to silica dust, and radiological alterations consistent with silicosis. The results from these patients were compared with those from normal subjects and smokers previously studied by the authors. RESULTS: Pulmonary function values were normal in most patients and not significantly different among groups. The median (range) rate of clearance of 99mTc-DTPA in smokers with silicosis was 4.1 (1.9-12.7) %/minute, which was higher than the rates in non-smoking patients with silicosis of 2.2 (1.1-6.6) %/minute and in smokers without exposure to silica dust of 2.9 (1.6-4.5) %/minute. These differences were more evident and significant when the clearance rates of the lower lobes of the three groups were compared. Clearance rates higher than 3%/minute were much more frequent in smokers with silicosis (85%) than in non-smoking patients with silicosis (15%) and in smokers (40%). CONCLUSION: In ceramic workers with radiographic changes resulting from exposure to silica dust, there is an additive effect of inhalation of silica dust and cigarette smoking on clearance rates of 99mTc-DTPA.

Mechanisms of hypercapnia in patients with chronic obstructive pulmonary disease (COPD)

A higher ventilatory drive evaluated by the inspiratory occlusion pressure (Poc) and a respiratory pattern characterized by smaller tidal volume (VT) and higher breathing frequency (f) was detected in patients with chronic obstructive pulmonary disease (COPD), in relation to normals. The purpose of this study was to identify the possible mechanisms involved in the development of hypercapnia in those patients, at rest and during exercise. We have studied 11 normocapnic (PaCO2 ( 45 mmHg) and 9 hypercapnic (PaCO2 > 45 mmHg) COPD patients. As expected, no difference in the ventilatory response and neural drive was detected between the two groups. However, the hypercapnic patients have higher values of serum HCO-3 and lower values of PaO2 at rest and values of the ratio dead volume to tidal volume (VD/VT) significantly higher at rest (0.67 vs. 0.55) and during exercise (0.54 vs. 0.38) in relation to normocapnic individuals. There was also a significant positive correlation at rest (r = 0.66*) and during exercise (r = 0.65*; *p < 0.05), between PaCO2 and VD/VT, identifying a decreased alveolar ventilatory efficiency, important in the development of hypercapnia in those patients. when the COPD patients were divided into two distinct groups (PaCO2 ( 40 and ( 50 mmHg), a respiratory pattern characterized by higher f and smaller VT was detected in the hypercapnic group during exercise. In conclusion, a higher VD/VT linked to alterations of the respiratory pattern (lower VT) and to inequalities of ventilation/perfusion (high V/Q areas), seems to explain the hypercapnia of our COPD patients, since the ventilatory response and neural drive were similar in normo and hypercapnic patients.

The effects of smoking and silica exposure on pulmonary epithelial permeability: a radioaerosol study with 99mTc-DTPA.

1. Pulmonary epithelial permeability (PEP) as evaluated by the clearance rate (K, %/min) of 99mTc-DTPA from lung to blood was measured in 4 groups of individuals: 10 normal controls; 10 smokers; 15 silica dust-exposed ceramic workers, 7 without chest X-ray alternations; and 8 with mild radiographic alterations, consistent with silicosis (small opacities of up to 1.5 mm diameter). 2. All subjects had normal pulmonary function tests. The mean clearance rates of smokers (3.0 %/min) and silica-exposed workers with X-ray changes (2.9 %/min) were accelerated compared to controls (1.2%/min) (P less than 0.05). Ceramic workers with normal X-rays had mean clearance rates (2.0 %/min) similar to controls. However, 3 of 7 (43%) had K values higher than the upper limit of the 95% confidence interval for the control mean. 3. Comparison of regional K (%/min) values with controls indicated faster clearance of 99mTc-DTPA in the upper lung regions of smokers. There was also increased clearance in the silicotic workers although of more uniform distribution over the lung regions analyzed. 4. Both smokers and ceramic workers exposed to a silica dust environment, with or without chest X-ray alterations, may show increased PEP compared to controls. As measurement of this parameter appears to be a sensitive index of lung injury, follow-up studies involving workers exposed to noxious dust are proposed to relate alterations in PEP to early silicosis and to the extent of lung injury.

Guillain-Barré syndrome after varicella-zoster infection. Case report.

The authors report a case of Guillain-Barrè syndrome (GBS) following a varicella infection in a 13 year-old boy. During his admission he developed respiratory insufficiency and dysautonomic events, as well as a severe sensitive peripheral neuropathy. Some aspects related to the etiology and pathogenesis of GBS are discussed.