Age-related mutations and chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

Recovery of function following unilateral denervation, but not unilateral decentralization, of the pineal gland as indicated by measurements of pineal melatonin content and urinary melatonin metabolites.

The rat pineal gland is an attractive system for studies on the capacity of neural systems to recover following partial injury, allowing both for the creation of precise subtotal lesions and for the measurement of recovery of function at the cellular level. The pineal gland receives overlapping sympathetic innervation from the right and left internal carotid nerves from neurons whose cell bodies are located in the two superior cervical ganglia. This innervation regulates several aspects of pineal metabolism in a circadian fashion, with the most dramatic being a marked increase in the night-time activity of N-acetyltransferase, a key enzyme regulating the rate of melatonin synthesis. We have previously shown that a highly divergent pattern takes place in the night-time activity of this enzyme following two different unilateral lesions of the sympathetic innervation to the gland. Thus, following a unilateral lesion of the internal carotid nerve (unilateral denervation), there is an initial decline in N-acetyltransferase activity; however, normal activity is again seen during the second and subsequent nights. In contrast, a unilateral lesion of the cervical sympathetic trunk, the nerve that innervates the superior cervical ganglion (unilateral decentralization), results in "permanent" impairment of N-acetyltransferase activity. In the present study, we report that the functional capacity of the entire pathway for melatonin synthesis is similarly affected following these lesions, as reflected by the levels of melatonin and of its precursor N-acetylserotonin in the pineal gland, as well as the levels of the main melatonin metabolite 6-hydroxy-melatonin in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Major cerebral vessels injury caused by a seatbelt shoulder strap: case report.

Major cerebral arterial injury may result from penetrating or blunt trauma. In blunt trauma, clinical suspicion of such injury may not be raised, especially if the cranial CT scan is negative. We report a case of a seatbelt shoulder strap to the neck resulting in injury to three major cerebral vessels as demonstrated by cerebral angiography. Although the initial cranial CT scans were negative, a cerebral infarction ultimately developed. The patient was managed conservatively and recovered most of her functions. The importance of clinical suspicion and cerebral angiography is stressed.

Inadequacy of predicted creatinine clearance as guide to chemotherapy.

Many chemotherapeutic agents are nephrotoxic and/or excreted via the kidney. Thus, careful evaluation of renal function is important since drug dosages are often lowered in patients with impaired renal function. When the creatinine clearance as calculated by the method of Cockcroft and Gault from the patient's age, weight, and serum creatinine was compared to the measured creatinine clearance in the same patients, the correlation coefficient was low (r = 0.40) and the average difference between the predicted and measured creatinine clearance values was 25.3%. Thus, in our patient population, creatinine clearance calculated by the method of Cockcroft and Gault did not correlate well with measured creatinine clearance and thus was not useful as a clinical tool.

MR imaging in the diagnosis of spontaneous spinal epidural hematomas.

Three patients with spontaneous (idiopathic) spinal epidural hematomas were diagnosed with magnetic resonance (MR) imaging. Magnetic resonance is an accurate, rapid method of localizing and characterizing the hematomas. We believe that MR (where available) should be the primary method of diagnosis in cases in which spinal epidural hematoma is suspected.

N-acetyl-beta-glucosaminidase and beta 2-microglobulin. Their urinary excretion in patients with renal parenchymal disease.

The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) and beta 2-microglobulin (beta 2M) was studied in 43 patients with various forms of renal parenchymal disease. Patients with membranous nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, obstructive pyelonephritis, nephrosclerosis, and minimal change nephropathy generally had urinary NAG and beta 2M levels more than 3 SDs above those seen in normal subjects. Patients with progressive renal disease averaged higher NAG and beta 2M urinary levels than those with the same renal lesion and stable function. Since elevated urinary levels of NAG and beta 2M suggest renal tubular injury or dysfunction, our observations suggest tubulointerstitial involvement in a wide variety of renal diseases.

Reversible "end-stage" lupus nephritis. Analysis of patients able to discontinue dialysis.

Seventeen of 41 patients with lupus nephritis who underwent dialysis for renal failure recovered renal function and discontinued dialysis. Two of these 17 had confounding factors unrelated to lupus that contributed to renal dysfunction (one meningococcemia, one vigorous diuresis). Indications for dialysis were identical both in patients who discontinued dialysis (short-term) and in those who did not (long-term). The rate of progression to dialysis, measured as the slope of the reciprocal of the serum creatinine level versus time, was significantly more rapid in the short-term group (p less than 0.001). Patients who underwent short-term dialysis were more likely to have had lupus for less than two years (p = 0.015). Anti-DNA antibody binding values, total hemolytic complement levels, extent of extrarenal disease, and hypertension did not differentiate the short-term from long-term dialysis groups. Renal biopsy performed within three months of first dialysis did not demonstrate a consistent picture in the short-term dialysis group. Dialysis is not equivalent to irrevocable end-stage renal disease in patients with lupus nephritis. Thirteen of 22 patients (59 percent) with a 10 percent reduction time for renal function of less than three weeks were able to discontinue dialysis. Ten of these 13 were alive without need for dialysis six months later, with a mean follow-up serum creatinine level of 2.9 +/- 1.9 mg/dl.

High-dose intravenous methylprednisolone pulse therapy in systemic lupus erythematosus.

To determine guidelines for treatment with high-dose intravenous methylprednisolone in lupus nephritis, we prospectively assessed the response to pulse therapy in 34 patients. In 12 of them, serum creatinine decreased by at least 20 percent within two months of treatment whereas in the remaining 22 there was no such response. Patients who responded were characterized by recent deterioration in function whereas nonresponders had had a more stable antecedent course (p = 0.003). Responders also had more diffuse lesions on renal biopsy (p = 0.028), had higher levels of anti-DNA antibodies (p less than 0.05), and tended to have higher titers of immune complexes and lower total hemolytic complement. High-dose intravenous methylprednisolone therapy may lead to striking improvement in renal function in lupus nephritis, especially in the subset of patients with recent antecedent functional deterioration. This improvement was maintained in 60 percent of the patients who responded for at least six months.

Proteinuria during long-term captopril therapy.

Proteinuria developed in six of 81 hypertensive patients given captopril for at least four months (protein excretion, greater than 200 mg/24 hr). Two had previously elevated protein excretion. In all patients the increased protein excretion occurred by the fourth month of treatment. It subsided in four after two to nine months, despite continued therapy. In two of the four, proteinuria cleared completely within seven months after onset, while in the other two it subsided to the range of 600 mg/24 hr. However, in the remaining two patients proteinuria persisted during captopril therapy and was associated with hypoalbuminemia and hypercholesterolemia. Renal biopsy specimens showed mild membranous nephropathy in two patients, one of whom had a remittance of proteinuria during continued captopril treatment.

Mesangial electron-dense deposits in membranous nephropathy.

In the absence of lupus, mesangial electron-dense deposits in membranous nephropathy are thought to be uncommon. In this study 18 renal biopsies of 16 cases seen over a 2-year period were evaluated by light and electron microscopy and immunofluorescence, directing particular attention to the mesangium. Lupus had been excluded in every instance by the usual serologic tests. In seven of the 18 biopsies, mesangial electron-dense deposits were found. Clinically, almost all of these patients were characterized by atypical features: five patients had underlying diseases which have been associated with membranous nephropathy (renal vein thrombosis, epidermoid carcinoma of the lung, SH-antigenemia, rheumatic heart disease and penicillamine therapy); there was one instance of spontaneous remission and another patient who progressed to terminal renal failure in less than 2 years. The results suggest that the presence of mesangial deposits in membranous nephropathy may be more common than has previously been suspected. This finding is not necessarily associated with systemic lupus erythematosus and may indicate an unusual or atypical form of membranous nephropathy.

Apparent acute renal failure associated with therapeutic aspirin and ibuprofen administration.

Aspirin and ibuprofen may cause a decrease in renal function which, although statistically significant, is usually small. We report a patient with active systemic lupus erythematosus and apparent acute renal failure associated with the administration of these drugs. Renal biopsy revealed no light microscopic evidence of drug nephrotoxicity although patchy nonspecific ultrastructural changes in the tubular epithelium were seen. The renal failure reversed rapidly when the drugs were withdrawn.

Cellular reactivity to altered glomerular basement membrane in glomerulonephritis.

Glomerular basement membrane may be altered during glomerulonephritis, exposing antigens that are recognized as foreign. Immunochemical studies suggest that removal of peripheral glycopeptides from the basement membrane with glycosidase mimics this pathogenetic event. To examine these hypotheses, we studied 24 patients with biopsy-proved glomerulonephritis by means of the lymphocyte-blast-transformation assay. Three preparations of normal glomerular basement membrane were used: two mimicked the native state for the peripheral glycopeptides, and one was altered by glycosidases. Results showed minimal differences in responses to native glomerular basement-membrane preparations among patients with glomerulonephritis and control groups. However, patients with glomerulonephritis had a significant blastogenic response to the glycosidase-treated glomerular basement membrane as compared to patients with nonglomerular renal disease and normal controls (P less than 0.0005). These studies suggest that cellular reactivity to altered glomerular basement-membrane antigens can be detected in certain forms of progressive glomerulonephritis.

Sterlization by laparoscopic tubal electrocoagulation a report of 1000 private patients.

PIP: In 1000 cases of sterilization by laparoscopic tubal electrocoagulation under general anesthesia with endotracheal intubation, no pregnancies have occurred in the follow-up period ranging from 5 to 57 months. The patients ranged from 17 to 50 years with a median of 31 years. 85% of the cases were done as outpatients; the surgical technic used was the standard 2 incision of Steptoe. 16.5% of the patients had had previous abdominal surgery; obesity was not considered a contraindication. There were 30 significant complications, the most common of which was mesosalpingeal bleeding, which occurred in 17 patients. Uterine perforation occurred in 9 patients, the Veress needle was inserted into the stomach of 2 patients. There was 1 traumatic transverse colon injury and 1 perforation of the sigmoid colon. The 3% complication rate of this study falls within the 0-8% reported in the literature. The complication rate falls as physician experience increases; in the last 42 consecutive months no major complications requiring celiotomy have occurred.^ieng