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Purpose Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). Patients and Methods Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m2 intravenous weekly × 4 doses and were then followed for response and progression; no maintenance therapy was provided. Results Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. Conclusion Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

The objectives of this study were to determine the effectiveness of a novel, trypsinized density gradient treatment designed to remove viruses from semen and to evaluate sperm viability after treatment. Exp. 1: Cryopreserved human semen (n = 6 donors) was layered on 2-mL columns of 45% Isolate (Irvine Scientific, Santa Ana, CA, USA) with or without 0.25% trypsin (trypsin-exposed and control, respectively), which overlaid 2-mL columns of 90% Isolate with or without 10 µg/mL soy-based trypsin inactivator (Sigma, St. Louis, MO, USA) and centrifuged (700g for 30 min). The layering of multiple density gradients is facilitated by a novel polypropylene tube insert, which also prevents contamination when extracting treated sperm (USA and international patents pending). Pellets were washed and then incubated at room temperature. Sperm were examined (motility and supravital staining) at 0, 2, 24, and 48 h post-treatment and the results evaluated using Wilcoxon Signed Rank and Rank Sum tests. Exp. 2: A cytopathic cell (MT-2) assay was conducted (6 replicates) to determine the effect of trypsin (1-min exposure) on HIV-1 RNA infectivity. Viral replication was assessed by syncytium formation and p24 antigen production. Exp. 3: Two pools of fresh human semen (N1 = 3 and N2 = 8 donors) were inoculated (1:1) with 1 × 108 copies/mL of cultured HIV-1 RNA, and one pool (N2) was inoculated (1:1) with plasma collected from patients infected with either Hepatitis B DNA (HBV) or C (HCV) RNA viruses; spiked and non-spiked aliquots were processed as in Exp. 1. Treated sperm pellets were analyzed for HIV-1 or HBV and HCV concentrations by the Bayer Versant branched DNA (bDNA; version 3.0) and/or the Roche Amplicor quantitative RT-PCR (1.5 ultrasensitive) assays at Toga Laboratories (Pty), Ltd. (Edenvale, South Africa). As a result of Exp. 1, there was significantly (P < 0.05) lower motility (but not supravital staining) between trypsin-treated and control sperm at 0 h (58.0 vs. 69.3%) and 2 h (54.7 vs. 62.9%) post-washing; however, no differences were noted after 24 h (P > 0.05). In Exp. 2, trypsin exposure affected HIV-1 RNA infectivity negatively as compared to controls in terms of MT-2 cell syncytium formation and p24 antigen production. Results of the bDNA and/or RT-PCR assays in Exp. 3 indicated that the procedure effectively reduced HIV-1, HBV, and HCV viral copies in the spiked semen samples to undetectable levels or levels below clinical relevance. In conclusion, the novel trypsin density gradient procedure was effective for removing HIV-1, HBV and HCV from spiked semen without markedly affecting sperm survival. Extrapolation of these results to natural infections may be unfounded for viruses (e.g. HBV) that are thought to integrate into sperm chromatin.

Cluster headache is the most severe of the primary headaches. Positron emission tomography and functional MRI studies have shown that the ipsilateral posterior hypothalamus is activated during cluster headache attacks and is structurally asymmetric in these patients. These changes are highly specific for the condition and suggest that the cluster headache generator may be located in that brain area; they further suggest that electrical stimulation of that region might produce clinical improvement in chronic cluster headache sufferers refractory to medical therapy. In five patients with severe intractable chronic cluster headache, hypothalamic electrical stimulation produced complete and long-term pain relief with no relevant side-effects. We therefore consider it essential to propose criteria for selecting chronic cluster headache patients for hypothalamic deep brain stimulation before this procedure is undertaken at other academic medical centres.

AbstractA number of surgical methods, including use of the long intestinal tube, have been designed to decrease the incidence of recurrent small bowel obstruction. The aim of the present study was to review the indications, morbidity, and long‐term results of the long intestinal tube at the Mayo Clinic. During the 12‐year period 1981–1992, 47 patients had such tubes placed. The patients formed a complex surgical group: 46 patients had previously undergone at least one laparotomy (median 4, range 1–10); 41 patients had been hospitalized at least once for small bowel obstruction (median 3, range 1–15); and all 41 of these patients had undergone at least one previous laparotomy for obstruction (median 2, range 1–7). Eleven patients had a history of inflammatory bowel disease, and eight had a history of irradiation. In addition to dense adhesions in 46 patients, operative findings included large bowel tumors in six patients, intraperitoneal carcinomatosis in four, intraabdominal abscess in four, and small bowel stricture in three. Twenty patients required either a small bowel or large bowel resection, and three had a stoma fashioned. Only one case of morbidity (tube retraction) was related to tube placement. Among the 36 patients with complete follow‐up, nine patients developed episodes of recurrent adhesional small bowel obstruction after a mean follow‐up of 48 months, although only one required laparotomy. Of the remaining 11 patients it is known that two developed small bowel obstruction, one of whom required laparotomy. Use of the long intestinal tube has generally been reserved for surgically complex cases. In light of the diverse and complicated nature of the patients in this series, the long‐term reoperation rate for adhesional small bowel obstruction appears to be low.

ABSTRACT OBJECTIVE To determine the clinical presentation, imaging characteristics, microscopic and ultrastructural characteristics, and treatment outcomes of patients with clinically silent pituitary corticotroph adenomas. METHODS All silent corticotroph adenomas diagnosed at the Mayo Clinic during the years 1975 through 1997 were selected from the files of the Mayo Tissue Registry. RESULTS We studied 23 cases, occurring in 16 male and 7 female patients (age range, 11–79 yr; mean age, 48 yr), who presented with headaches (50%), visual field defects (61%), extraocular muscle paresis (13%), hypopituitarism (26%), and galactorrhea/amenorrhea (43%/29% of the female patients). No patients exhibited clinical hypercortisolism. All tumors were macroadenomas (2.4 ± 0.8 cm; range, 1.5–4.0 cm) and exhibited suprasellar extension in 87% of the cases and hemorrhage, necrosis, and/or cystic changes in 61%. All tumors stained were variably periodic acid-Schiff-, adrenocorticotropic hormone-, and β-endorphin-positive, particularly Subtype I lesions. Ultrastructural classification was performed in 19 cases. In a comparison of Subtype I and II tumors, differences were observed with respect to sex (male/female, 1.4:1 versus 6:1), preoperative hyperprolactinemia (5 of 16 versus 0 of 6 cases), preoperative hypopituitarism (9 of 16 versus 5 of 7 cases), radiographic or gross invasion (7 of 16 versus 5 of 7 cases), and partial or total postoperative pituitary failure (6 of 16 versus 6 of 6 cases). The overall median postoperative follow-up period was 4.9 years (range, 0.3–16.6 yr); 54% of the patients had persistent or recurrent tumors. CONCLUSION Clinically silent corticotroph adenomas behave in an aggressive manner and are characterized by the following: lack of clinical signs or symptoms of Cushing's syndrome and normal cortisol levels; no or only minor elevations of serum adrenocorticotropic hormone levels; macroadenomas with hemorrhagic infarction; and presentation dominated by mass effect symptoms. The high persistence/recurrence rate underscores the need for long-term follow-up.

Very long chain fatty acid dehydrogenase (VLCAD) deficiency is a rare but treatable cause of cardiomyopathy, fatty liver, skeletal myopathy, pericardial effusions, ventricular arrhythmias, and sudden death. Unrecognized, VLCAD deficiency may be rapidly progressive and fatal, secondary to its cardiac involvement. Because early diagnosis improves outcome, we present a neonate with VLCAD deficiency in whom retrospective analysis of the newborn screening card revealed that a correct diagnosis could have been made by newborn screening using tandem mass spectrometry. Our patient demonstrated a classic neonatal course with transient hypoglycemia at birth, interpreted as culture-negative sepsis, followed by a quiescent period notable only for hypotonia and poor feeding. At 3 months, he presented with cardiorespiratory failure and pericardial effusions, requiring pericardiocentesis, tracheostomy, and prolonged mechanical ventilation. Plasma free-fatty acid and acylcarnitine profiles demonstrated small but significant elevations of C14:2, C14:1, C16, and C18:1 acylcarnitine species, findings consistent with a biochemical diagnosis of VLCAD deficiency. Enteral feeds were changed to Portagen formula with marked improvement in cardiac symptoms over several weeks. To confirm the biochemical diagnosis, molecular analysis was performed by analysis of genomic DNA on a blood sample of the patient. Sequencing analysis and delineation of VLCAD mutations were performed using polymerase chain reaction and genomic sequencing. The patient was heterozygous for 2 different disease-causing mutations at the VLCAD locus. The maternal mutation was a deletion of bp 842–3 in exon 8, causing a shift in the reading frame. The paternal mutation was G+1A in the consensus donor splice site after exon 1; this splice-site mutation would likely result in decreased mRNA. The likely consequence of these mutations is essentially a null phenotype. To determine whether this case could have been picked up by tandem mass spectrometry analysis at birth when the patient was asymptomatic, acylcarnitine analysis was performed on the patient's original newborn card (after obtaining parental consent, the original specimen was provided courtesy of Dr Kenneth Pass, Director, New York State Newborn Screening Program). The blood sample had been obtained at 1 week of age and stored at room temperature for 6 months and at 70°C thereafter for 18 months. Electrospray tandem mass spectrometry used a LC-MS/MS API 2000 operated in ion evaporation mode with the TurboIonSpray ionization probe source. The acylcarnitine profile obtained from the patient's original newborn card was analyzed 2 years after it was obtained. In comparison with a normal control, there was a significant accumulation of long chain acylcarnitine species, with a prominent peak of tetradecenoylcarnitine (C14:1), the most characteristic metabolic marker of VLCAD deficiency. This profile would have likely been even more significant if it had been analyzed at the time of collection, yet 2 years later is sufficient to provide strong biochemical evidence of the underlying disorder. Discussion. VLCAD was first discovered in 1992, and clinical experience with VLCAD deficiency has been accumulating rapidly. Indeed, the patients originally diagnosed with long chain acyl-CoA deficiency suffer instead from VLCAD deficiency. The phenotype of VLCAD deficiency is heterogeneous, ranging from catastrophic metabolic and cardiac failure in infancy to mild hypoketotic, hypoglycemia, and exertional rhabdomyolysis in adults. This case demonstrates that VLCAD deficiency could have been detected from the patient's own neonatal heel-stick sample. Most likely, a presymptomatic diagnosis would have avoided at least part of a lengthy and intensive prediagnosis hospitalization that had an estimated cost of $400 000. Although VLCAD is relatively rare, timely and correct diagnosis leads to dramatic recovery, so that detection by newborn screening could prevent the onset of arrhythmias, heart failure, metabolic insufficiency, and death. Fatty acid oxidation defects, including VLCAD deficiency, may account for as many as 5% of sudden infant death patients. Recent instrumentation advances have made automated tandem mass spectrometry of routine neonatal heel-stick samples technically feasible. Pilot studies have demonstrated an incidence of fatty acid oxidation defects, including short chain, medium chain, and very long chain acyl-CoA dehydrogenase deficiencies, of approximately 1/12 000. As a result, cost-benefit ratios for this approach should be systematically examined.

There has been increasing recognition of the detrimental impact of peripheral arterial disease (PAD) on the health of Americans, and yet there is no common national program of public PAD education designed to diminish this impact. To heighten awareness of this problem, a 2-day PAD Public Education Strategy Meeting was recently attended by representatives of 17 professional societies and public health associations whose missions support the prevention, diagnosis, treatment, and rehabilitation of vascular diseases. This Public Education Strategy Meeting was intended to provide the rationale and structure to create a national PAD public awareness campaign to diminish the health impact of PAD, and to improve cardiovascular outcomes in the USA. This paper: (1) provides the rationale for creation of a national PAD public education program; (2) reviews the development and success of national hypertension, hypercholesterolemia, and Women’s Heart Health public education programs as models of educational efficacy; (3) elucidates how the work of many vascular professionals has led to a national consensus for creation of a national PAD public educational program; (4) provides an overview of the National Heart, Lung and Blood Institute PAD education meeting; and (5) outlines the ‘next steps’ required to accomplish these goals. This meeting achieved consensus that we share responsibility for developing accurate, unified messages to promote PAD awareness and improved care. Participants agreed that the creation of such messages should be linked to plans to disseminate them to all Americans at risk. A consensus was reached that such messages, when commonly created and offered to the public, are most likely to achieve the rewards in better health that all Americans deserve. The Vascular Disease Foundation, a not-for-profit foundation whose mission includes public education regarding the prevention, diagnosis, treatment, and rehabilitation of PAD, will devote its resources to guide a new coalition in this process and to create a national PAD awareness campaign. During 2003 and 2004, the coalition will create the organizational underpinnings and timeline for what will undoubtedly be a multi-year effort. In conclusion, participants of the Public Education Strategy Meeting agreed to create a broad coalition to develop a national PAD public awareness program, with the objectives to develop and disseminate public education messages on PAD. A successful national PAD education program will contribute to the creation of a broader mandate to improve global cardiovascular health in the USA.