Diverticular disease

Diverticular disease is a common finding in Western countries with an increasing prevalence with age. Many patients with the disorder remain asymptomatic. However, up to 30% of those affected may show clinical signs including pain, bleeding, obstruction, abscess, fistulae and perforation. The purpose of this chapter is to review the epidemiology, pathogenesis, clinical presentation, diagnostic regimens and treatment options for this disorder.     

Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1

Cytogenetic analysis of acute lymphoblastic leukemia (ALL) of childhood identified nonrandom chromosomal abnormalities of the short arm of chromosome 12. The alterations include deletions that are thought to be indicative of the presence of a tumor suppressor gene that is mutated on the remaining allele. To refine further the chromosomal localization of this gene, we analyzed the loss of heterozygosity (LOH) of chromosome 12 in 100 primary ALL samples using 22 polymorphic markers and identified two distinct smallest common deleted regions on chromosome 12p13. One region is flanked by D12S77 and D12S98 and has a size of 4 cM. Twenty-six percent of informative patients showed LOH in this region. This region may contain the TEL gene. The other region is flanked by D12S269 and D12S308 including the KIP1 gene. Forty-four percent of informative patients showed LOH in this second region. Mutational analysis of KIP1 using polymerase chain reaction-single- strand conformation polymorphism analysis and Southern blot analysis showed no homozygous deletions and point mutations suggesting that the altered gene in this second region is not the KIP1. Clinical data showed that LOH of 12p was demonstrated more frequently in precursor-B ALLs (32 of 80; 40%) than in T-ALLs (1 of 20; 5%) (P = .0027). Furthermore, patients with 12p LOH were younger (P = .013), with a lower DNA index (P = .046), but they had the same survival rates at 3 years. In summary, these data suggest that two different tumor suppressor genes are on chromosome arm 12p, which act separately in the development of childhood precursor-B ALLs. One of the tumor suppressor genes is in the region the KIP1 gene, but our data suggest this gene is not abnormal. The other target is in the region of the TEL gene; and this candidate deserves further study.     

Aortic valve sclerosis, mitral annular calcium, and aortic root sclerosis as markers of atherosclerosis in men

Aortic valve sclerosis (AVS) and mitral annular calcium (MAC) as detected by transthoracic echocardiography have been associated with atherosclerosis. Aortic root sclerosis (ARS) may have a similar association, but has not been studied. This study evaluates, by transesophageal echocardiography, the association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. Multiplane transesophageal echocardiography with evaluation of AVS, MAC, ARS, and aortic atheromatous disease by 2 experienced observers unaware of clinical data was performed in 157 male patients > or =50 years old. The presence of cardiovascular disease, defined as coronary, carotid, or peripheral artery disease, was determined by specific criteria. The prevalence of AVS, MAC, ARS, and aortic atheromatous disease was 42%, 30%, 48%, and 71%, respectively. The presence of AVS, MAC, or ARS was highly associated with aortic atheromatous disease (odds ratio 4.9 to 12.0, confidence interval 1.4 to 35.8, p <0.001). ARS was also associated with cardiovascular disease (odds ratio 2.2, confidence interval 1.0 to 4.5, p = 0.038). The presence of AVS, MAC, or ARS had a sensitivity of 77%, specificity of 72%, a positive predictive value of 88%, and a negative predictive value of 55% for aortic atheromatous disease. We concluded that the prevalence of AVS, MAC, or ARS by transesophageal echocardiography in men is common, and their presence is highly associated with aortic atheromatous disease and coronary, carotid, or peripheral artery disease.     

Randomized trial of once-weekly parathyroid hormone (1-84) on bone mineral density and remodeling

CONTEXT: Daily PTH administration increases bone mineral density (BMD) and reduces fracture risk. However, cost and compliance significantly limit clinical use. OBJECTIVE: Our objective was to determine whether less frequent PTH administration increases lumbar spine BMD. PARTICIPANTS, DESIGN, AND SETTING: Fifty postmenopausal women ages 45-70 yr with femoral neck BMD T-score between -1.0 and -2.0 participated in a double-blind, randomized, placebo-controlled trial at St. Joseph Hospital, Bangor, ME. INTERVENTION: Subjects received sc injections of daily PTH(1-84) (100 mug) or placebo for 1 month, followed by weekly injections (PTH or placebo) for 11 months. OUTCOMES: Change in lumbar spine dual-energy x-ray absorptiometry areal BMD (primary) was assessed. Secondary outcomes included volumetric BMD at spine and hip by quantitative computed tomography, trabecular bone microarchitecture by magnetic resonance imaging of distal radius, and biochemical bone turnover markers. RESULTS: At 12 months, lumbar spine areal BMD increased 2.1% in PTH-treated women compared with placebo (P = 0.03). Vertebral trabecular volumetric BMD increased 3.8% in PTH-treated women compared with placebo group (P = 0.08). PTH-treated women also had higher distal radial trabecular bone volume, number, and thickness compared with placebo-treated women (P < 0.04). After 1 month of daily PTH, N-terminal propeptide of type I collagen (P1NP) was markedly increased compared with placebo (P < 0 .0001), and a difference persisted, although lessened, throughout the study. Bone resorption indices were unchanged in PTH-treated women and were reduced in the placebo group. CONCLUSION: Once-weekly PTH after 1 month of daily treatment increases spine BMD, radial trabecular bone, and bone formation markers in postmenopausal women. These results suggest that less frequent alternatives to daily PTH dosing for 2 yr could be effective. Additional studies are required to define the optimal frequency of PTH administration.     

Nd:YAG Laser Therapy for Gastrointestinal Bleeding Due to Radiation Colitis

Significant uncontrollable gastrointestinal bleeding due to radiation colitis has in the past required colectomy, proctectomy, arterial ligation, or angiographic embolization for control. The use of Nd:YAG laser photocoagulation of mucosal vascular ectasias provides a promising safe alternative to such invasive therapies.     

The Older HIV-Positive Adult: A Critical Review of the Medical Literature

Older adults make up an ever-growing proportion of human immunodeficiency virus (HIV) cases in the United States, with approximately 25% of infections occurring in adults over the age of 50 years. Although there is a preliminary body of literature addressing the socioeconomic and prognostic issues of HIV infection in older adults, very little rigorous scientific research has looked at the significant clinical issues relevant to this growing population. Treatment of older adults is complicated by an increased prevalence of medical comorbidities, but little is known about the effects of complicated medication regimens in this group, as they are routinely excluded from clinical trials of newer HIV medications. The delay in diagnosis and treatment of HIV in older adults has led to poorer outcomes, including lower baseline CD4 counts, decreased time to acquired immune deficiency syndrome diagnosis, and increased mortality. Despite these facts, there is mounting evidence that timely diagnosis and treatment of HIV in older adults leads to improved outcomes, similar to younger patients. This review evaluates the literature focusing on HIV and older adults.     

Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy

PURPOSE: Before the development of highly active antiretroviral therapy for the treatment of HIV infection, HIV patients diagnosed with invasive squamous-cell carcinoma of the anal canal carried a very poor prognosis. This study was designed to determine the outcome in a similar group of patients in the era of highly active antiretroviral therapy.METHODS: HIV-positive patients treated for invasive squamous-cell carcinoma of the anal canal at the University of Texas Medical Center affiliated hospitals from 1980 to 2001 were identified from operative data and cancer registries. We reviewed these records and collected data regarding age, CD4 count, highly active antiretroviral therapy, cancer treatment, complications, and survival. The patients were divided into two groups based on the presence or absence of highly active antiretroviral therapy and compared using a Kaplan-Meier approach.RESULTS: Fourteen patients with HIV and invasive squamous-cell carcinoma of the anal canal were identified. Six were in the prehighly active antiretroviral therapy group and eight in the highly active antiretroviral therapy group. All were considered for treatment with chemotherapy and radiation. In the prehighly active antiretroviral therapy group, one patient refused therapy and three were unable to complete the squamous-cell carcinoma therapy as planned because of complications. Four of eight highly active antiretroviral therapy patients were unable to complete the squamous-cell carcinoma therapy as planned. The prehighly active antiretroviral therapy patients had a mean age of 40 years and a mean CD4 count of 190 at the time of diagnosis. The highly active antiretroviral therapy patients had a mean age of 44 years and a mean CD4 count of 255 at the time of diagnosis. The 24-month survival was 17 percent in the prehighly active antiretroviral therapy group and 67 percent in the highly active antiretroviral therapy group (P = 0.0524). All six patients in the prehighly active antiretroviral therapy group died with active squamous-cell carcinoma vs. two in the highly active antiretroviral therapy group. Four of the remaining six patients had no evidence of active squamous-cell carcinoma at the last follow-up visit.CONCLUSIONS: A review of patients with HIV and invasive squamous-cell carcinoma of the anal canal suggests a trend toward a higher CD4 count at the time of diagnosis and improved survival in patients receiving highly active antiretroviral therapy. In this new era, HIV-positive patients should be on highly active antiretroviral therapy. If not, highly active antiretroviral therapy should be initiated, and standard multimodality therapies for invasive squamous-cell carcinoma of the anal canal are recommended.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Anal sphincter reconstruction in the elderly: Does advancing age affect outcome?

PURPOSE: This study was designed to determine whether advancing age affects outcome after anal sphincter reconstruction. METHOD: Anal sphincter reconstruction, performed on patients 55 years of age and older, was reviewed to determine if functional outcome was adversely affected by advancing age. A subgroup of patients was studied with anal manometry before and after repair and with pudendal nerve terminal motor latency (PNTML) before surgery. Results were compared with a younger group of patients. RESULTS: Between July 1986 and July 1991, 14 patients, ages ranging from 55 to 81, underwent anal sphincter reconstruction using an overlapping muscle repair. Ten patients were incontinent of solid stool and four of liquid stool. Improvement was seen in 13 of 14 patients: 7 (50 percent) complete control, 3 (21 percent) incontinent to flatus, and 4 (29 percent) incontinent to liquid stools (including the patient who failed to improve). Ten patients were studied with a continuous pull-out manometric technique and PNTML: one was not improved. There was minimum change in mean maximum resting pressure (35.0–37.9 mmHg). Mean maximum squeezing pressure increased from 66 to 75 mmHg overall. Patients with complete control had a mean maximum squeezing pressure of 81 mmHg compared with 60 mmHg in patients with residual incontinence. Mean anterior anal sphincter length increased from 2.92 cm to 331 cm. PNTML was normal (2.0±0.2) on one or both sides in all nine patients who improved (average, 2.1). The patient who failed to improve had abnormal nerve function bilaterally (2.4, 2.7). CONCLUSION: Anal sphincter reconstruction can be performed in elderly patients with improvements in the majority of patients. Total control can be achieved by restoring maximum squeezing pressure in a patient with normal pudendal nerve function.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, San Francisco, California, June 7 to 12, 1992.     

Nitric oxide and bone: The phoenix rises again

The involvement of nitric oxide (NO) in preventing bone loss has long been hypothesized, but despite decades of research the mechanisms remain obscure. In this issue of the JCI, Jin et al. explored NO deficiency using human cell and mouse models that lacked argininosuccinate lyase (ASL), the enzyme involved in synthesizing arginine and NO production. Osteoblasts that did not express ASL produced less NO and failed to differentiate. Notably, in the context of Asl deficiency, heterozygous deletion of caveolin 1, which normally inhibits NO synthesis, restored NO production, osteoblast differentiation, glycolysis, and bone mass. These experiments suggest that ASL regulates arginine synthesis in osteoblasts, which leads to enhanced NO production and increased glucose metabolism. After a period when research slowed, these studies, like the legendary phoenix, renew the exploration of NO in bone biology, and provide exciting translational potential.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.