Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity.

Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50-300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.     

Flexible Sigmoidoscopy Screening in an Industrial Setting

Little is known about the yield of colorectal cancer screening programs in an industrial setting. We therefore established a flexible sigmoidoscopy screening program at a chemical manufacturing plant and offered testing to all employees over the age of 40. After a Fleet enema preparation had been administered, a digital rectal examination and sigmoidoscopy were performed on each volunteer worker in the medical office of the plant. The plant had an average census of about 650 workers; 202 were screened during a 2-yr period. The mean (+/- SEM) age of participants was 52 +/- 0.4. Sixty-four employees had polyps (31.7%); data on follow-up colonoscopy were available in 69%. Colonoscopy revealed adenomatous polyps in 23 workers (53.5%), hyperplastic polyps in 10 (23%), and no evidence of neoplasia in 10 (23%). Seven workers did not arrange for follow-up colonoscopy and 12 individuals could not be contacted. No cancers were detected. In the 40- to 50-yr age group, polyps were detected in 19.5% of employees (25% adenomatous). Incidental findings were common, and included prostatic nodules, hemorrhoids, diverticulosis, and proctitis, among others. We conclude that screening sigmoidoscopy can be conveniently and economically performed at the workplace, with a high yield and good worker acceptance. The high yield suggests a possible association between polyp formation and work in a chemical plant. The finding of adenomatous polyps in the younger patients suggests that the threshold for flexible sigmoidoscopy at age 50 needs to be reassessed.     

Chronic trapezius myalgia. Morphology and blood flow studied in 17 patients

Bilateral open biopsies from the painful upper part of the trapezius muscle were studied in 17 patients with localized chronic myalgia related to static load during repetitive assembly work. Isolated pathologic ragged red fibers were related to the presence of myalgia. The phenomenon indicating disturbed mitochondrial function was confined to the Type 1 fibers. Using a laser-Doppler flowmeter, the muscle blood flow was recorded in the exposed muscle before a biopsy was taken. Pain was assessed and graded as the difference between the two sides, as was the presence of ragged red fibers. The myalgia correlated with reduced local blood flow: the greater the pain difference, the greater the reduction in blood flow. There was a correlation between the presence of mitochondrial changes and reduced muscle blood flow.     

Assessment of MRI criteria for abnormal brain MRI in acute monosymptomatic optic neuritis. Comparison to findings in healthy persons

To evaluate various MRI criteria we studied a representative group of 149 consecutive patients below 50 years with acute monosymptomatic optic neuritis (AMON), a frequent first manifestation of multiple sclerosis (MS). The presence, number, size, and localization of areas of increased signal (AIS) on T₂-weighted brain MRIs obtained at 1.5 T were described and compared with findings in 71 healthy persons aged 21–50 years without diabetes, cerebrovascular or neurologic diseases. MRI was performed within 2–145 days, median 16 days from onset of AMON and showed from 0 to 26 AIS, sized 2–30 mm, in 79 of 149 (53%) patients compared to 0–18 AIS, sized 2–12 mm, in 31 of 71 (44%) healthy persons. In patients, AIS were significantly more frequent in women than in men (χ² = 4.67, p > 0.05). Periventricular AIS were revealed in 70 (47%) patients and in 14 (20%) healthy persons. Subcortical AIS were present in 5 (3%) patients and in 18 (25%) healthy persons. Infratentorial AIS were present in only 3 (2%) patients. The sensitivity and specificity of previously proposed diagnostic MRI criteria for MS were unsatisfactory in our group of patients and have previously only been validated in definite MS. We therefore constructed and tested four new sets of criteria. The set with the best relation between sensitivity (e.g. 41%) and specificity (e.g. 93%) was the following: presence of two or more AIS, of which at least one is periventricular or infratentorial, combined with the absence of subcortical AIS. These criteria are recommended for patients with AMON and might be used in other patients with possible or probable MS.     

Determination of functional kidney volume by single-photon emission computed tomography in patients with insulin-dependent diabetes mellitus.

Functional parenchymal kidney volume was determined by single-photon emission computed tomography (SPECT) for 99mTc-dimercaptosuccinic acid (DMSA) using a rotating gamma camera in phantom experiments and in patients with insulin-dependent diabetes mellitus (IDDM). The results from the patient examinations were corrected according to the phantom studies and were thereafter set in relation to renal haemodynamics, blood pressure, and urinary albumin excretion. Functional parenchymal kidney volume was significantly greater in diabetic patients compared to that of 11 healthy controls (P < 0.003). Urinary albumin excretion was increased and glomerular filtration rate (GFR) per renal parenchymal volume significantly less in patients with a duration of diabetic disease of more than 15 years compared to patients with shorter duration of disease (P < 0.03 and P < 0.05 respectively). Diabetic patients with a GFR of more than 120 ml/min had greater renal parenchymal volume than patients with lower GFR (P < 0.02). Patients with increased GFR, renal plasma flow (RPF), renal blood flow, or filtration fraction had significantly greater functional parenchymal volume than the healthy subjects (P < 0.01 for all comparisons). We conclude that by application of SPECT for DMSA we were able to show that IDDM patients have greater renal parenchymal volumes than healthy subjects. GFR/kidney volume was increased in IDDM patients with a duration of disease of < 15 years compared to patients with long-standing diabetes. The SPECT technique seems suitable for prospective long-term follow-up studies of functional kidney volume in IDDM patients.     

Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea-cycle-based and idiopathic aetiologies

Summary We report two female patients, one with a known inborn error of ureagenesis and the other of unknown cause, in whom recurrent, transient episodes of severe hyperammonaemia increased in frequency and severity with sexual maturity and parturition. Both responded to ovarian steroids administered continuously to suppress ovulation and menstruation, and ultimately to simple hysterectomy. These studies suggest a new therapeutic approach to defective ureagenesis in female patients and a relationship between ammonia production or disposal and the menstrual cycle.     

Dummy- and finger-sucking habits in young Swedish and Norwegian children.

The prevalence of dummy- and finger-sucking habits in 3-yr-old children was registered in four different areas of Sweden and Norway. In Norway 245 children were examined and in Sweden 171 children. The Swedish children were more prone to develop a dummy-sucking habit as well as to prolong it. About 10-19% of the children in the different groups become finger-suckers. Very few of these finger-suckers had stopped sucking at 3 yr of age. The highest rate of non-suckers was found among the children from Karasjok/Kautokeino in northern Norway, who were mainly of Lappish origin.     

Anomalies of digastric muscles: CT and MR demonstration

Anomalies of the anterior bellies of the digastric muscles were described during the 19th century and have been of little clinical significance. However, new imaging modalities, such as ultrasound, CT, and magnetic resonance (MR) imaging, can easily depict muscle anatomy without having to rely on dissection studies. The anterior bellies of the digastric muscles were evaluated in 40 patients having CT and 35 patients having MR imaging of the oropharynx. An accessory muscle crossing the midline between two normal digastric muscles was found in a patient in the MR imaging group. In the CT group, one patient showed absence of one anterior belly; in its place a small muscle was seen passing from the hyoid bone to the midline raphe of the mylohyoid muscle. It is necessary to recognize that muscle variants of the digastric muscle occur, to avoid confusion with abnormal lesions of the floor of the mouth and the submental space.     

Excitability in free muscle transfers: an optimal method of monitoring tissue circulation?

Recent methods of postoperative monitoring of free muscle transfers were used in 4 patients operated on with free revascularized gracilis muscle. The contractility/electromyographic (EMG) activity in response to electrical stimulation was used as an index of viability, i.e., intact circulation. However, during operations it was observed that contractions as well as EMG potentials could be evoked 1 to 2 hours after blood flow had been arrested. Muscle excitability was further studied in the gracilis muscle from a patient who had undergone hemipelvectomy; it was found that contractility and EMG potentials were evoked at least 4 hours after circulatory arrest. It thus seems that loss of muscle excitability is not as early a sign of impaired blood supply as recently has been suggested. Spontaneous EMG activity, which can be recorded 2 to 3 weeks after denervation, is reported to be affected earlier than muscle excitability by circulatory arrest. Thus, the recording of spontaneous EMG activity in previously denervated muscles is proposed as an alternative and simple electrophysiological method for post-operative monitoring of vascularization in free muscle transfers.     

Increased NADPH-diaphorase activity in canine myxomatous mitral valve leaflets

Comparable pathological changes in the mitral valve have been described in dogs, pigs and human patients with myxomatous mitral valve disease (MMVD), i.e., primary mitral valve prolapse. The progressive myxomatous changes are probably a response to repeated impact on the leaflets, and endothelial stress or damage probably plays a central role in the pathogenesis. Little, however, is known about the vasoactive substances that mediate the subendothelial changes. The aim of this study was to investigate the expression of nitric oxide synthase (NOS) in canine mitral valve leaflets and to relate the findings to MMVD changes. The mitral valve was taken post mortem from 12 dogs (six males and six females) and a whole valve NADPH (the reduced form of nicotinamide-adenine dinucleotide phosphate) diaphorase (NADPH-d) reaction was performed. Macroscopical (semiquantitative) and microscopical (computer image analysis) evaluations of the staining due to NADPH-d activity were performed at four specific areas of the valve and related to microscopical signs of MMVD and gross signs of thickening or prolapse, or both. Macroscopically, the NADPH-d colour grade was correlated with the degree of MMVD (P=0.01). In addition, endothelial NADPH-d staining intensity was correlated with macroscopical signs of disease (P=0.004) as well as with collagen degeneration (P=0.008) and deposition of mucopolysaccharides (P=0.02). Age, gender and specific area of the valve did not seem to influence the NADPH-d activity. In conclusion, increased NADPH-d activity, suggesting increased NOS expression, was found in areas of the mitral valve with myxomatous changes. This indicates that nitric oxide (NO) may play a role in the pathogenesis of MMVD in dogs.