Deep cerebral invasion by basal cell carcinoma of the scalp

We report recurrent basal cell carcinoma of the scalp with deep cerebral invasion in an 82-year-old man. Plain films and CT showed extensive, full thickness, skull destruction at the vertex. Gadolinium-enhanced MRI revealed neoplastic invasion of the meninges and left cerebral hemisphere, down to the lateral ventricle. We postulate that tumour extended into the brain along perivascular spaces of transcerebral vessels. This hypothesis is supported by the cleft-like contrast enhancement on MRI.     

Long-term follow-up of the modified Delorme procedure for rectal prolapse

HYPOTHESIS: The modified Delorme operation is a safe, effective, and durable treatment for complete rectal prolapse. DESIGN: Retrospective analysis of outcomes in adult patients undergoing the modified Delorme operation. SETTING: Community-based tertiary referral center with a 5-year general surgery residency program. PATIENTS: A total of 52 consecutive patients undergoing surgery for the treatment of complete rectal prolapse during the 26-year period ending December 2001. INTERVENTIONS: Modified Delorme operation.Main Outcomes Measured Method of anesthesia, morbidity, mortality, recurrence rates, length of follow-up, and incontinence. RESULTS: In the 52 patients, the mean length of prolapse was 8.2 cm. The mean operating time was 75 minutes. Forty-five patients were administered general anesthesia, 4 were administered spinal anesthesia, and 3 were administered local anesthesia. The mean postoperative stay was 4.9 days for 1975 through 2001 and 2.8 days for 1990 through 2001. No patients died as a result of the procedure. Patients were followed up for 61.4 months. Major medical comorbidities occurred in 40 patients. Preoperative incontinence was present in 12 patients, 10 of whom improved after the procedure, and postoperative incontinence in 8. The recurrent postoperative prolapse rate at 5 years was 6% (3/52) and the recurrent postoperative prolapse rate to the end of the study was 10% (5/52). Two patients (4%) had complications that required operative intervention in the postoperative period. CONCLUSIONS: The modified Delorme operation is a safe and effective surgical treatment for complete rectal prolapse. The risk of recurrent prolapse is low, and the procedure may be safely performed in patients with significant medical comorbidities.     

Preliminary experience with inhaled milrinone in cardiac surgery

Background: Inhaled administration of milrinone reduces pulmonary artery pressure. Pulmonary hypertension (PH) and right heart failure are associated with difficult separation from cardiopulmonary bypass (CPB). Therefore, inhaled milrinone could facilitate separation from CPB. Objective: To determine the impact and timing of administration of inhaled milrinone. Methods: A retrospective analysis of our experience on high-risk patients receiving inhaled milrinone was conducted to evaluate the postoperative course after administration of the drug. Results: Seventy-three patients received inhaled milrinone from June 2002 to February 2005. Mean age was 64 ± 13 years, with a mean preoperative Parsonnet score of 27 ± 14. Inhaled milrinone (5 mg) was administered before (n = 30) or after (n = 40) CPB, three patients had off-pump procedures and were excluded. CPB time was 145 ± 78 min with cross-clamping times of 91 ± 56 min without any significant difference between groups. Fifty-four patients (74%) had difficult separation from CPB, 14 patients (19%) required an intra-aortic balloon pump and 10 patients (14%) needed emergency reinitiation of CPB for hemodynamic instability. Ten patients died in the perioperative period (13.7%). Patients receiving inhaled milrinone prior to CPB initiation had a lowering pulmonary artery pressure after CPB (p < .01) and had less emergency reinitiation of CPB after weaning (3% vs 23%, p = .02) as compared to those with administration after CPB. No detectable side effects were directly linked to the administration of the drug. Conclusion: In this high-risk cohort, use of inhaled milrinone was well tolerated. Administration before initiation of CPB could help weaning from CPB.     

Prevalence of protein malnutrition in children maintained on peritoneal dialysis

A paucity of outcome measures exist for children, making evidence-based treatment guidelines difficult to establish. Serum albumin has been identified as a surrogate marker for nutritional status and morbidity/mortality in patients with end-stage renal disease (ESRD). We hypothesized that the prevalence of low serum albumin (<2.9 g/dl) in children on peritoneal dialysis (PD) may be greater, making this population at risk. Patient data were collected prospectively over 24 months (1999-2000) from all children (1-18 years) maintained on either hemodialysis (HD) or PD within the six-state New England area; 64 observations were made on 39 children on PD over the 2-year period. The mean age was 11.7+/-4.7 years (mean+/-SD). The prevalence of low serum albumin in children was 35.9% (23/64 observations) compared with 19.5% (712/3,719 observations) in adult Network ESRD patients on PD ( P<0.004). None of the 32 children (47 observations) maintained on HD exhibited low serum albumin during the data collection period. The prevalence of low serum albumin in adult HD patients was 5.5%. Dietary protein intake was estimated from a calculated protein catabolic rate (PCR). PCRs in children treated with both PD and HD were similar, averaging 1.1+/-0.4 g/kg per day (mean+/-SD). Thus, children maintained on PD are at greater risk of protein malnutrition compared with peers treated with HD and adults on PD or HD. A PCR of approximately 1 g/kg per day may not be adequate to maintain nutrition.     

Sympathetic Neural Adaptation to Hypocaloric Diet With or Without Exercise Training in Obese Metabolic Syndrome Subjects

OBJECTIVE

Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function.

RESEARCH DESIGN AND METHODS

Untreated men and women (mean age 55 ± 1 year; BMI 32.3 ± 0.5 kg/m²) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks.

RESULTS

Body weight decreased by −7.1 ± 0.6 and −8.4 ± 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 ± 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by −96 ± 30 and −101 ± 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by −12 ± 6 and −19 ± 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups.

CONCLUSIONS

The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.The metabolic syndrome (MetS) is an increasingly prevalent multidimensional risk factor for cardiovascular disease and type 2 diabetes (1). Its etiology is complex and incompletely understood, but thought to involve the interplay between metabolic susceptibility, lifestyle factors, and the acquisition of excess visceral adiposity (2). Scientific studies performed over the last 2 decades strongly support the relevance of the sympathetic nervous system (SNS) in both the pathogenesis and target organ complications of MetS obesity (3).Several indexes of SNS activity, such as urinary norepinephrine excretion, norepinephrine spillover from sympathetic nerves, and postganglionic muscle sympathetic nerve activity (MSNA) are increased in subjects with MetS, even in the absence of hypertension (4–7). Among the adiposity indexes, abdominal visceral fat is most strongly associated with elevated MSNA (8). Because of the bidirectional relationship between sympathetic activation and insulin resistance, much debate has focused on their chronology. Prospective studies with 10–20 years follow-up indicate that elevated plasma norepinephrine concentration (9) and sympathetic reactivity (10) precede and predict future rise in BMI and development of insulin resistance. Although seemingly counterintuitive, sympathetic activation may be causally linked to obesity via β-adrenoceptor desensitization (11) and insulin resistance (12,13). In established obesity, metabolic, cardiovascular (baroreflex impairment), and medical conditions (obstructive sleep apnea) contribute significantly to sympathetic neural drive and further aggravate insulin resistance, hence establishing a vicious cycle (3,7). Chronic sympathetic activation is associated with an increased prevalence of preclinical cardiovascular and renal changes that are recognized predictors of adverse clinical prognosis (3,14,15).Weight loss and exercise are recommended as first-line treatments for MetS. The Diabetes Prevention Program and the Oslo Diet and Exercise Study have shown the marked clinical benefits of intensive lifestyle intervention on the resolution of the MetS (16,17). Individually, both weight loss (5) and exercise training (18,19) cause sympathoinhibition and improvement in MetS components. We have previously reported that moderate weight loss (7% of body weight) by diet alone is accompanied by reductions in whole-body norepinephrine spillover and MSNA and improvement in spontaneous cardiac baroreflex function in middle-aged MetS subjects (5). Because exercise is often added to energy restriction in the treatment of obesity, it is pertinent to clarify its additive benefits. Augmented improvements in metabolic, anthropometric, and cardiovascular parameters have been observed after combined exercise training and dietary weight loss in some (17,20,21), but not other studies (22), and there are limited data regarding their combined effect on sympathetic activity (23). Exercise training may potentially augment weight loss induced sympathoinhibition by promoting a greater loss of fat relative to lean mass (20,21), by further improvement in insulin sensitivity (24) and reduction in plasma leptin concentration (21), and by potentiation of baroreceptor sensitivity (18).The present study was conducted to 1) test the hypothesis that weight loss by combined hypocaloric diet and aerobic exercise training would be associated with greater sympathoinhibition and improvement in MetS components than hypocaloric diet alone and 2) to examine the interrelationships between reduction in sympathetic tone and concurrent changes in anthropometric, metabolic (insulin sensitivity, plasma leptin concentration), and cardiovascular parameters. A moderate-intensity bicycle riding protocol was chosen as the exercise intervention, based on an earlier study that demonstrated attenuation in whole-body and renal norepinephrine spillover rates with this regimen in healthy men (19).     

Syk‐Induced Phosphatidylinositol‐3‐Kinase Activation in Epstein–Barr Virus Posttransplant Lymphoproliferative Disorder

Posttransplant lymphoproliferative disorder (PTLD)‐associated Epstein–Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV‐associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol‐3′‐kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV‐infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib‐treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV‐associated malignancies.     

Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase

Hypophosphatasia (HPP) is a rare inherited disorder characterized by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic-based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10-year period and performed mutation screening of ALPL in those with low ALP (≤40 U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had potentially pathogenic variants in ALPL. Eight of these individuals were heterozygous for mutations previously described in HPP and 2 were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including 4 with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss-of-function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Long-term results of corneal graft survival in infants and children with peters anomaly

OBJECTIVE: To determine the long-term results of corneal graft survival after penetrating keratoplasty for Peters anomaly and to identify risk factors for graft failure. DESIGN: Noncontrolled interventional case series: a single-center retrospective review of a consecutive surgical series. PARTICIPANTS: The records of all children 12 years of age or younger who underwent penetrating keratoplasty for Peters anomaly between January 1971 and December 1992 were reviewed. All study eyes had completed a minimum of 3 years of follow-up from the date of first keratoplasty and had undergone most of their corneal surgery at Emory University. INTERVENTION: Characteristics of the recipient, the eye, the donor, and the surgical procedure were analyzed for their influence on survival of the first graft. Survival probabilities were estimated using the Kaplan-Meier method. Multivariate regression analysis was performed to estimate relative risks and adjusted survival probabilities. MAIN OUTCOME MEASURE: Graft clarity. RESULTS: One hundred forty-four penetrating keratoplasties were performed in 72 eyes of 47 patients. The median age at first keratoplasty was 4.4 months. The median follow-up was 11.1 years. Fifty-four percent of eyes received one graft, 18% received two grafts, and 28% received three or more grafts. The overall probability of maintaining a clear first graft was 56% at 6 months, 49% at 12 months, 44% at 3 years, and 35% at 10 years. The probability of second or subsequent grafts surviving for 3 years was less than 10%. Thirty-nine percent of eyes had a clear graft at the time of review; 36% of eyes had a clear first graft. Multivariate analysis identified disease severity, donor cornea size, coexisting central nervous system abnormalities, and quadrants of anterior synechiae as the strongest risk factors for graft failure. Supplemental multivariate analysis, restricted to observable preoperative variables, identified stromal vessels, total limbal opacification, and preoperative glaucoma as independent preoperative predictors of graft failure. Allograft rejection was the most frequently identified cause of graft failure. Major complications after keratoplasty were phthisis, retinal detachment, cataract, and glaucoma. CONCLUSIONS: The overall long-term probability of maintaining a clear graft after initial penetrating keratoplasty for Peters anomaly is 35% +/- 0.06%, with subsequent grafts rarely surviving. Eyes with severe disease, larger donor corneas, coexisting central nervous system abnormalities, and anterior synechiae have significantly poorer outcomes than eyes without these factors. These data should be carefully considered before recommending corneal transplantation for Peters anomaly, particularly after previous graft failure.