Metabolic and target organ outcomes after total pancreatectomy: Mayo Clinic experience and meta‐analysis of the literature

Introduction Total pancreatectomy (TP) has been associated with substantial metabolic abnormalities and poor glycaemic control limiting its use. Because data reported to date are limited, we evaluated outcomes related to the diabetes mellitus obligated by TP. Methods A case series study of all patients who underwent TP from 01/01/1985 to 12/31/2006 at Mayo Clinic was conducted. TP cases were summarized according to perioperative procedures, mortality and morbidity after TP. To complement this retrospective examination, a survey was developed to measure DM treatment modality, target organ failure and complications in patients alive in 2007. We performed a meta‐analysis to compare our results with similar previous studies and provide overall estimates of outcomes. Results A total of 141 cases were studied (97 malignant diseases, 44 benign diseases). The median survival was much less for malignant pathology (2·2 vs 8·7 years, Log rank P = 0·0009). In 2007, there were 59 patients that were presumed alive and 47 (80%) responded to the survey. Mean HbA1c at last follow‐up was 7·5% with 89% of respondents on a complex insulin programme (mean daily insulin requirement 35 ± 13 units). Episodic hypoglycaemia was experienced by 37 (79%); 15 (41%) experienced severe hypoglycaemia. In contrast, diabetic ketoacidosis developed in only 2 (4%). Target organ complications and chronic diarrhoea developed in 13 patients (28%) each. Conclusion The primary factor determining survival after TP is the aetiology necessitating TP, i.e. pancreatic malignancy. Most respondents used complex insulin programmes, but hypoglycaemia continues to be a problem.     

Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide,Ac-hE18A-NH2

Apolipoprotein E (apoE) exerts prominent anti-inflammatory effects and undergoes recycling by target cells. We previously reported that the peptide Ac-hE18A-NH₂, composed of the receptor binding domain (LRKLRKRLLR) of apoE covalently linked to the Class A amphipathic peptide 18A, dramatically lowers plasma cholesterol and lipid hydroperoxides and enhances paraoxonase activity in dyslipidemic animal models. The objective of this study was to determine whether this peptide, analogous to apoE, exerts anti-inflammatory effects and undergoes recycling under in vitro conditions. Pulse chase studies using [¹²⁵I]-Ac-hE18A-NH₂ in THP-1 derived macrophages and HepG2 cells showed greater amounts of intact peptide in the cells at later time points indicating recycling of the peptide. Ac-hE18A-NH₂ induced a 2.5-fold increase in preβ-HDL in the conditioned media of HepG2 cells. This effect persisted for 3 days after removal of the peptide from culture medium. Ac-hE18A-NH₂ also induced the secretion of cell surface apoE from THP-1 macrophages. In addition, the peptide increased cholesterol efflux from THP-1 cells by an ABCA1 independent mechanism. Moreover, Ac-hE18A-NH₂ inhibited LPS-induced vascular cell adhesion molecule-1 (VCAM-1) expression, and reduced monocyte adhesion in human umbilical vein endothelial cells (HUVECs). It also reduced the secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from THP-1 macrophages even when administered post-LPS and abolished the 18-fold increase in LPS-induced mRNA levels for MCP-1 in THP-1 cells. Taken together, these results suggest that addition of the putative apoE receptor-domain to the Class A amphipathic peptide 18A results in a peptide that, similar to apoE, recycles, thus enabling the potentiation and prolongation of its anti-atherogenic and anti-inflammatory effects. Such a peptide has great potential as a therapeutic agent in the management of atherosclerosis and other inflammatory diseases.     

Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life

We studied morphine pharmacokinetics after a single intravenous dose of 0.1 mg/kg in 20 newborn infants, who were born at 26 to 40 weeks of gestation and were less than 5 days of age. In the 10 infants whose gestational age was less than or equal to 30 weeks, the mean (+/- SD) distribution half-life was 50 +/- 35 minutes, elimination half-life was 10 +/- 3.7 hours, and clearance was 3.39 +/- 3.28 ml/kg/min; the corresponding values for the three term infants were 19 +/- 8 minutes, 6.7 +/- 4.6 hours, and 15.5 +/- 10 ml/kg/min, respectively. The data suggested a trend of decreasing values for distribution and elimination half-lives with increasing gestation, but a considerable degree of variation was seen. The morphine clearance rate increased as a function of gestational age at a rate of 0.9 ml/kg/min per week of gestation. Between 18% and 22% of the drug was found to be protein bound. Four hours after the dose, the drug level remained greater than or equal to 12 ng/ml in 8 of 10 infants born at greater than or equal to 31 weeks of gestation. In 8 of 10 infants born at less than or equal to 30 weeks of gestation, similar levels were maintained at 8 hours after the initial dose. We conclude that (1) there is a marked degree of variation in morphine pharmacokinetics during the neonatal period, (2) nearly 80% of the intravenously infused drug remains free, which might explain the high sensitivity to morphine in this age group, and (3) during the first week of age, adequate blood levels can be maintained by administration of morphine at 4- to 6-hour intervals in term infants and at less frequent intervals in very premature infants (less than or equal to 30 weeks of gestation).     

Mutational analysis of the RB1 gene in Indian patients with retinoblastoma

Twenty-one probands, twelve with bilateral and nine with unilateral retinoblastoma, were screened for mutations in the RB1 gene using genomic DNA from peripheral blood leukocytes as well as tumors. Amplification of individual exons and flanking regions of the RB1 gene were carried out, followed by direct sequencing of the amplified products. Sequences of affected individuals were compared with those of controls. Mutations were identified in seven patients, five with bilateral and two with unilateral retinoblastoma. Six out of seven mutations involved the formation of premature termination codons by means of single base substitutions (2), frameshifts due to splice-site mutations (2), or deletion and duplication (2). One missense mutation was identified. Of the remaining fourteen patients, seven with bilateral disease had no mutations in peripheral blood (7 cases) or tumors (3/7 cases). Analysis of the peripheral blood of seven patients with unilateral disease also showed no mutations. Mutations were detected in about one-third of the cases, suggesting that hemizygous deletions at the RB1 locus or mutations outside the coding regions of RB1 may be responsible for the disease in the remaining patients.     

Protective effect of adenosine against neuronal injury induced by middle cerebral artery occlusion in rats as evidenced by diffusion-weighted imaging

In the present study, adenosine, an inhibitory neuromodulator, was studied in male Wistar rats subjected to 2 h of transient middle cerebral artery (MCA) occlusion. Adenosine (500 mg/kg ip) was administered twice-once at the time of MCA occlusion and again at the time of reperfusion-and evaluated for its protective effect by using diffusion-weighted imaging (DWI) (30 min after reperfusion). After the DWI experiments, one group of animals was euthanized 2 h after reperfusion for the estimation of oxidative stress markers, while in another group, neurological deficit was assessed 24 h after MCA occlusion. In the adenosine-treated group, percent hemispheric lesion area (%HLA) in DWI was significantly attenuated (11.7+/-5.2) as compared to vehicle-treated group (21.4+/-4.7). The level of malondialdehyde (MDA) (301.8+/-22 nmol/g wet tissue) in the adenosine-treated group was significantly decreased as compared to that in the vehicle-treated MCA-occluded rats (420+/-20 nmol/g wet tissue). An insignificant change was observed in the levels of glutathione in both the vehicle-treated MCA-occluded and the adenosine-treated groups. The neurological deficit was significantly improved in the adenosine-treated group (1.8+/-0.06) as compared to the vehicle-treated (2.9+/-0.38) group. This is the first study to demonstrate the effectiveness of adenosine using DWI in the MCA-occluded rats.     

An epidemiological study of pulmonary function tests in geriatric population of central India

We have studied Pulmonary Function Tests (PFTs) namely Vital Capacity (VC). Forced Vital Capacity (FVC), and Forced Expiratory Volume in First Second (FEV1). Forced Expiratory Flow(FEF 25-50%) in 1200 elderly subjects above 60 years of age of which 570 were females and 630 males. Mean age was 69.22 +/- 5.57 years in males and 68.77 +/- 5.44 in females. The mean value of ventilatory parameters were as follows-1) VC 2.99 +/- 0.5 lt in males and 1.89 +/- 0.29 lt in females. 2) FVC 2.69 +/- 0.58 lt. in males and 1.76 +/- 0.21 lt in females. 3) FEV1/FVC% 83.82 +/- 10.62% in males and 83.37 +/- 11.93% in females. 4) FEF 25-75% was 2.81 +/- 1.20 lt/sec in males and 2.13 +/- 1.27 lt/sec. Physical as well as ventilatory parameters were less in females than for males. The correlation of age with VC and FEV1 was highly significant (P < 0.01) but with FVC was not significant (P > 0.05). The correlation of height, weight and body surface area was not significant with any ventilatory parameter (P > 0.05). Multiple regression equations for VC, FVC and FEV1 were formulated for males and females taking height and age as variables. The predicted values correlated excellently with observed values.     

Tumor-specific novel taxoid-monoclonal antibody conjugates

Taxoids bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody immunoconjugates were designed, synthesized and their activities evaluated. A highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in severe combined immune deficiency mice, resulting in complete inhibition of tumor growth in all the treated mice.     

Decline in rate of colonization of oligodendrocyte progenitor cell (OPC)-depleted tissue by adult OPCs with age

Rates of remyelination decline with age and this has been attributed to slower recruitment of oligodendrocyte progenitor cells (OPCs) into areas of demyelination and slower differentiation of OPCs into remyelinating oligodendrocytes. When considering causes for reduced recruitment rates, intrinsic causes (alterations in biological properties of OPCs) need to be separated from extrinsic causes (age-related differences in the lesion environment). Using 40 Gy of X-irradiation to deplete tissue of its endogenous OPC-population, we examined the effects of age on the rate at which adult rat OPCs colonize OPC-depleted tissue. We found a significant reduction in the rate of colonization between 2 and 10 months of age (0.6 mm/week versus 0.38 mm/week). To determine if this represented an intrinsic property of OPCs or was due to changes in the environment that the cells were recolonizing, OPCs from 10-month-old animals were transplanted into 2-month-old hosts and OPCs from 2-month-old animals were transplanted into 10-month-old hosts. These experiments showed that the transplanted OPCs retained their age-related rate of colonization, indicating that the decline in colonizing rates of OPCs with age reflects an intrinsic property of OPCs. This age-related decline in the ability of OPCs to repopulate OPC-depleted tissue has implications for understanding remyelination failure in multiple sclerosis (MS) and developing therapies for remyelination failure.     

Evaluation of cosmetic tattooing in localised stable vitiligo

Thirty patients with localised stable vitiligo were selected from the Out Patient Department for cosmetic tattooing. Of them, 19 cases (63.3%) had skin patches, 9 cases (30%) had mucosal patches, and 2 cases (6.7%) had both skin and mucosal involvement. After complete clinical evaluation, cosmetic tattooing was performed on these patients, and they were followed up for 6 months. As results, 23 cases (76.7%) had excellent color matching, 2 cases (6.7%) had good color matching, and 5 cases (16.6%) had pigment shedding. Excellent results were seen in all mucosal patches. Dark complexion cases showed better results than fair complexion ones.