"Hairy cell" leukemia: a heterogeneous chronic lymphoproliferative disorder.

Thirteen patients with “hairy cell” leukemia and circulating tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells were studied. A high percentage of peripheral mononuclear cells from 12 patients were positive for surface membrane immunoglobulin (Smlg). Unlike studies in chronic lymphocytic leukemia, in most of these patients with “hairy cell” leukemia it was not possible to establish “clonality” on the basis of λ/κ or immunoglobulin-class cell surface markers because of frequent weak reactions with more than one antiserum in each group. Complement (C₃) receptor-bearing cells accounted for 69 per cent of the peripheral mononuclear cells in one patient. In another patient, 80 per cent of the peripheral mononuclear cells were positive for Fc receptors. Both patients also had high levels of Smlg-positive cells. In a third patient, peripheral mononuclear cells were of T-cell type as determined by over 80 per cent E rosetting and only 2 per cent Smlg-bearing cells. Phytohemagglutinin (PHA) stimulation on peripheral mononuclear cells from five patients revealed weak responses at three days. However, when this response was followed further, it reached normal intensity by five days of incubation, in contrast to cells from patients with chronic lymphocytic leukemia which gave a peak PHA response at eight to nine days. Cells from all patients, except cells from patients with T-cell type “hairy cell” leukemia, showed positive cytotoxic reactions with antiserums designating various B-cell (Merrit; la-like) alloantigenic groups. “Hairy-cell leukemia” appears to be a heterogeneous group of chronic lymphoproliferative disorders.     

The rat pineal gland comprises an endocannabinoid system

In the mammalian pineal gland, the rhythm in melatonin biosynthesis depends on the norepinephrine (NE)-driven regulation of arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme of melatonin biosynthesis. A recent study showed that phytocannabinoids like tetrahydrocannabinol reduce AANAT activity and attenuate NE-induced melatonin biosynthesis in rat pineal glands, raising the possibility that an endocannabinoid system is present in the pineal gland. To test this hypothesis, we analyzed cannabinoid (CB) receptors and specific enzymes for endocannabinoid biosynthesis or catabolism in rat pineal glands and cultured pinealocytes. Immunohistochemical and immunoblot analyses revealed the presence of CB1 and CB2 receptor proteins, of N-acyl phosphatidyl ethanolamine hydrolyzing phospholipase D (NAPE-PLD), an enzyme catalyzing endocannabinoid biosynthesis and of fatty acid amide hydrolase (FAAH), an endocannabinoid catabolizing enzyme, in pinealocytes, and in pineal sympathetic nerve fibers identified by double immunofluorescence with an antibody against tyrosine hydroxylase. The immunosignals for the CB2 receptor, NAPE-PLD, and FAAH found in pinealocytes did not vary under a 12 hr light:12 hr dark cycle. The CB1 receptor immunoreaction in pinealocytes was significantly reduced at the end of the light phase [zeitgeber time (ZT) 12]. The immunosignal for NAPE-PLD found in pineal sympathetic nerve fibers was reduced in the middle of the dark phase (ZT 18). Stimulation of cultured pinealocytes with NE affected neither the subcellular distribution nor the intensity of the immunosignals for the investigated CB receptors and enzymes. In summary, the pineal gland comprises indispensable compounds of the endocannabinoid system indicating that endocannabinoids may be involved in the control of pineal physiology.     

Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial

OBJECTIVEThe effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities.RESULTSOf the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (−9.55 [95% CI −15.21, −3.90] vs. −15.38 [95% CI −16.64, −14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants’ brain MRI scans.CONCLUSIONSOur study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.     

Determinants of Weight Gain in the Action to Control Cardiovascular Risk in Diabetes Trial

OBJECTIVE

Identify determinants of weight gain in people with type 2 diabetes mellitus (T2DM) allocated to intensive versus standard glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

RESEARCH DESIGN AND METHODS

We studied determinants of weight gain over 2 years in 8,929 participants (4,425 intensive arm and 4,504 standard arm) with T2DM in the ACCORD trial. We used general linear models to examine the association between each baseline characteristic and weight change at the 2-year visit. We fit a linear regression of change in weight and A1C and used general linear models to examine the association between each medication at baseline and weight change at the 2-year visit, stratified by glycemia allocation.

RESULTS

There was significantly more weight gain in the intensive glycemia arm of the trial compared with the standard arm (3.0 ± 7.0 vs. 0.3 ± 6.3 kg). On multivariate analysis, younger age, male sex, Asian race, no smoking history, high A1C, baseline BMI of 25–35, high waist circumference, baseline insulin use, and baseline metformin use were independently associated with weight gain over 2 years. Reduction of A1C from baseline was consistently associated with weight gain only when baseline A1C was elevated. Medication usage accounted for <15% of the variability of weight change, with initiation of thiazolidinedione (TZD) use the most prominent factor. Intensive participants who never took insulin or a TZD had an average weight loss of 2.9 kg during the first 2 years of the trial. In contrast, intensive participants who had never previously used insulin or TZD but began this combination after enrolling in the ACCORD trial had a weight gain of 4.6–5.3 kg at 2 years.

CONCLUSIONS

Weight gain in ACCORD was greater with intensive than with standard treatment and generally associated with reduction of A1C from elevated baseline values. Initiation of TZD and/or insulin therapy was the most important medication-related factor associated with weight gain.Weight gain is a well-known consequence of the intensive treatment of type 2 diabetes mellitus (T2DM) (1). However, the definition of intensive therapy varies, and no studies have attempted near-normal glycemia, as in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Furthermore, some currently available therapies have a greater effect on weight, although the key determinants of weight gain in relation to intensive therapy remain unclear. Therefore, data from this trial could give us insight into the determinants of weight gain with intensive therapy.The ACCORD trial randomized 10,251 people with type 2 diabetes and other cardiovascular risk factors to one of two glycemic targets: 1) an intensive A1C target of <6.0%; or 2) a standard target of between 7 and 7.9% (2). Participants were followed for a mean of 3.5 years until the intervention was stopped due to increased mortality in the intensive group. During this follow-up period, weight was measured regularly, and participants in the intensive group experienced greater weight gain than participants in the standard group. The data collected in the ACCORD trial provide an opportunity to identify determinants of weight gain in people with T2DM allocated to intensive versus standard glycemic control and to assess the relationship between changes in glycemic control and changes in weight.The main outcomes of the ACCORD trial were previously reported (2). We present results on 8,929 participants (4,425 randomized to the intensive arm and 4,504 to the standard arm) with valid data at baseline and at least 2 years of follow-up. Participants who were not included did not have weights or withdrew or died during the first 2 years. In this analysis, we focus on weight gain as the dependent variable and describe the time course of weight change, its relationship to baseline characteristics and allocated treatment arm (intensive and standard), and its relationship to the postrandomization change in glycemic control (A1C) and use of glucose-lowering medications.We posed several questions regarding potential causes of weight gain during the first 2 years of the trial, and the differences in weight gain experienced by the two allocated groups. First, was weight gain explained by the baseline characteristics (including prior medications)? Second, was weight gain explained by the change in A1C? Third, was weight gain explained by postrandomization medication use? Finally, were the factors that led to the change in weight the same in the intensive and standard groups?     

Cryptococcus neoformans Chemotyping by Quantitative Analysis of 1H Nuclear Magnetic Resonance Spectra of Glucuronoxylomannans with a Computer-Simulated Artificial Neural Network

The complete assignment of the proton chemical shifts obtained by nuclear magnetic resonance (NMR) spectroscopy of de-O-acetylated glucuronoxylomannans (GXMs) from Cryptococcus neoformans permitted the high-resolution determination of the total structure of any GXM. Six structural motifs based on an α-(1→3)-mannotriose substituted with variable quantities of 2-O-β- and 4-O-β-xylopyranosyl and 2-O-β-glucopyranosyluronic acid were identified. The chemical shifts of only the anomeric protons of the mannosyl residues served as structure reporter groups (SRG) for the identification and quantitation of the six triads present in any GXM. The assigned protons for the mannosyl residues resonated at clearly distinguishable positions in the spectrum and supplied all the information essential for the assignment of the complete GXM structure. This technique for assigning structure is referred to as the SRG concept. The SRG concept was used to analyze the distribution of the six mannosyl triads of GXMs obtained from 106 isolates of C. neoformans. The six mannosyl triads occurred singularly or in combination with one or more of the other triads. The identification and quantitation of the SRG were simplified by using a computer-simulated artificial neural network (ANN) to automatically analyze the SRG region of the one-dimensional proton NMR spectra. The occurrence and relative distribution of the six mannosyl triads were used to chemotype C. neoformans on the basis of subtle variations in GXM structure determined by analysis of the SRG region of the proton NMR spectrum by the ANN. The data for the distribution of the six SRGs from GXMs of 106 isolates of C. neoformans yielded eight chemotypes, Chem1 through Chem8.     

Evidence for in vitro senescence of T-lymphocytes cultured from normal human peripheral blood

Long-term T-cell cultures from 15 donors of various ages were established using T-cell growth factor (TCGF). The donors were divided in equal numbers into three age groups, under 40, 40 to 80 and over 80 years of age. The cell cultures showed a growth pattern similar to the Hayflick Phenomenon observed in the cultured human fibroblasts with a limited total number of doublings. Cell cultures from younger groups grew longer with higher total number of doublings. The total number of doublings averaged 16.5, 12.2 and 6.5 for the cultured cells obtained from donors under 40, 40 to 80 and over 80 years of age respectively.     

Association of HLA—B8, DRw3, and Anti-Acetylcholine Receptor Antibodies in Myasthenia Gravis

Twenty-eight patients with myasthenia gravis (MG), five with and 23 without thymoma, and 47 normal controls were typed for serologically defined HLA-A, B, C, and DRw antigens. Sera from all patients were titered for antibodies to acetylcholine receptors (AChR). The frequency of HLA-B8 and DRw3 in the non-thymoma MG patients was significantly higher than in the normal population. Most of the non-thymoma patients with AChR titers higher than the average level were positive for HLA-B8 and/or DRw3, while the majority of the HLA-B8(-) and/or DRw3(-) non-thymoma patients demonstrated AChR titers below average. These findings support the possibility of the existence of immune response genes in the HLA-B, DRw segment of the major histocompatibility complex which are concerned in the response to or recognition of autoantigens.     

Rat liver adenyl cyclase activity in various thyroid states

Thyroidectomized and euthyroid rats were injected with three doses of triiodothyronine (T(3)) or of the diluent over a 6 day period, and liver homogenates were assayed for basal, epinephrine-stimulated, and NaF-stimulated adenyl cyclase activity. Based on NaF-stimulated levels, total adenyl cyclase activity, expressed per milligram of liver protein, was increased after thyroidectomy. Administration of T(3) to either hypothyroid or euthyroid rats, however, had no effect on the NaF-stimulated levels. Basal and epinephrine-stimulated enzyme activities were the same in hypothyroid, euthyroid, and hyperthyroid (euthyroid + T(3)) liver homogenates. In contrast, injections of T(3) in hypothyroid rats increased the activities of basal and epinephrine-stimulated adenyl cyclase. In view of the findings in euthyroid and hyperthyroid liver, it is possible that this effect is transient. In general, no correlation was found between the effects of thyroid hormone on respiration and on adenyl cyclase activity of the rat liver. These results imply that the hepatic thermogenic response to thyroid hormone is not mediated by stimulation of adenyl cyclase activity with the possible exception of the early effects of T(3) in the athyroid rat.