Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates.

Understanding SARS-CoV-2 associated immune pathology is crucial to develop pan-effective vaccines and treatments. Here we investigate the immune events from the acute state up to four weeks post SARS-CoV-2 infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. We show a robust migration of CD16 expressing monocytes to the lungs occurring during the acute phase, and we describe two subsets of interstitial macrophages (HLA-DR+CD206-): a transitional CD11c+CD16+ cell population directly associated with IL-6 levels in plasma, and a long-lasting CD11b+CD16+ cell population. Trafficking of monocytes is mediated by TARC (CCL17) and associates with viral load measured in bronchial brushes. We also describe associations between disease outcomes and high levels of cell infiltration in lungs including CD11b+CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages is long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios show less severe illness. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.

A "Double-Diamond Superlattice" Built Up of Cd17S4(SCH2CH2OH)26 Clusters.

A simple preparation of Cd(17)S(4)(SCH(2)CH(2)OH)(26) clusters in aqueous solution leads to the formation of colorless blocky crystals. X-ray structure determinations revealed a superlattice framework built up of covalently linked clusters. This superlattice is best described as two enlarged and interlaced diamond or zinc blende lattices. Because both the superlattice and the clusters display the same structural features, the crystal structure resembles the self-similarities known from fractal geometry. The optical spectrum of the cluster solution displays a sharp transition around 290 nanometers with a large absorption coefficient ( approximately 84,000 per molar per centimeter).

Molecular analysis of MLL-1/AF4 recombination in infant acute lymphoblastic leukemia.

We examined ten cases of acute lymphoblastic leukemia (ALL) in infants (less than 1 year of age) by RT-nested PCR for a MLL-1/AF4 rearrangement. Five patients revealed a positive result. The specific PCR product differed in size from approximately 380-670 bp indicating various splicing variants in the MLL-1/AF4 rearrangement. Three patients had a fusion between exon 6 of the MLL-1 gene and codon 362 of the known AF4 cDNA sequence. Moreover, in two patients more than one specific PCR product was detected, possibly due to alternative splicing. In the first case, sequencing of these products revealed a hybrid mRNA consisting of MLI-1 exon 7 or exon 8, respectively, fused to the AF4 gene at codon 348. In the second case with alternative splicing, again, exon 7 or 8 of the MLL-1 gene were fused to the AF4 gene as in case 1. The AF4 sequence involved in this patient, however, started at codon 362. The AF4 break was, therefore, identical to the three MLL-1/AF4 positive patients as described above. Moreover, we investigated all ten patients for the reciprocal mRNA transcript AF4/MLL-1 by a similar PCR approach. In none of these patients, including the five MLL-1/AF4 positive cases was a specific PCR product obtained. However, in the MV411 cell line bearing a t(4;11), which served as a positive control in our MLL-1/AF4-PCR assay, the reciprocal AF4/MLL-1 mRNA was detected. Our results indicate that a MLL-1/AF4 rearrangement occurs in about 50% of infants with ALL. In contrast, the reciprocal hybrid mRNA can only rarely be detected, if at all.

Detection of four different 11q23 chromosomal abnormalities by multiplex-PCR and fluorescence-based automatic DNA-fragment analysis.

A nested polymerase chain reaction (PCR) protocol was developed for rapid detection of four different 11q23 abnormalities by a single PCR assay. During each of the two PCR rounds a sense primer located within exon 5 of the MLL gene at 11q23 was combined with four different antisense primers, each located within possible translocation partner genes at chromosomes 4, 6, 9, and 19, respectively. Except for the MLL primer all primers used during the second round of nested-PCR carried a characteristic fluorescence label at their 5'-end. Agarose gel analysis of the PCR products was sufficient to discriminate between the absence of any of the four MLL rearrangements and the presence of at least one of them. Discrimination of the four different MLL translocation partner genes was not possible by agarose gel analysis due to a molecular heterogeneity of the 11q23 breakpoints resulting in PCR products of variable size. For this reason, automatic fluorescence-based DNA-fragment analysis was used to exactly define the MLL translocation partner genes if a positive result had been obtained by agarose gel analysis. In patients with leukemia, this assay may enable a fast and highly sensitive detection of different 11q23 abnormalities, which usually correlate with poor clinical prognosis.

Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study).

OBJECTIVE: The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-controlled, double-blind, two-center pilot study. MATERIAL AND METHODS: Forty inpatients (23 male, 18 female, age range 18 - 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician's and the patient's own assessment were documented. RESULTS: A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ. CONCLUSION: This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.

Temporal orientation and education. A direct relationship in normal people.

Neurologists usually do not take socioeconomic status into account when evaluating temporal orientation. Our data indicate that this is a mistake: temporal orientation related directly to education, one measure os socioeconomic level, in New Jersey residents. The neurologist should suspect an abnormality in temporal orientation for patients with (1) some college training and (2) no education beyond high school, if they misstate the day of the month by more than one or three days, respectively.

Effect of the laser ridge on posterior capsule opacification.

The most common complication of extracapsular cataract extraction is posterior capsule opacification, which appears to result from the proliferation of anterior lens epithelium onto the posterior capsule. The presence of a posterior chamber intraocular lens has been shown to decrease the incidence of posterior capsule opacification, possibly by a barrier mechanism. This retrospective clinical study compares the effect of two different lens designs (with and without a laser ridge) on posterior capsule opacification requiring Nd:YAG laser posterior capsulotomy. Twenty-one of 101 patients (20.8%) with nonridged lenses required Nd:YAG laser posterior capsulotomies versus 13 of 86 patients (15.1%) with ridged lenses. Although these data showed a clinical benefit from using a ridged lens, no statistical difference in the incidence of posterior capsulotomy was noted. Further evaluation of capsular-optic surface apposition is needed.

The KID Study V: the natural history of type 2 diabetes in younger patients still practising a profession. Heterogeneity of basal and reactive C-peptide levels in relation to BMI, duration of disease, age and HbA1.

In a detailed evaluation of the data accumulated for 493 type 2 diabetics who participated in the KID Study, pre- and postprandial C-peptide was correlated with blood glucose level, HbA1, body mass index (BMI), duration of disease and age. As described earlier the KID-Study examined a younger cohort of type 2 diabetics predominately practising a profession. Our investigations demonstrate a significant increase of pre- as well as postprandial C-peptide levels with increasing obesity. However, delta C-peptide, as an indicator at the reaction capacity of pancreatic secretion, decreases significantly and continuously. Pre- as well as postprandial C-peptide levels decrease significantly with up to 15-20 years duration of disease. The preprandial pancreatic secretion is usually even at a high normal level at such a late stage whereas the secretory reserve of normal or mildly overweight as well as of obese type 2 diabetics is more impaired. In contrast to patients with a BMI < 30, obese patients with a BMI > 30 will also develop impairment of basal insulin secretion over decades. The patient's age did not influence the pre- or postprandial insulin secretion. The quality of metabolic control as measured by the HbA1 has nearly exclusive impact on the secretory reserve capacity. Correlation with increasing HbA1 concentrations, the postprandial but not the preprandial C-peptide levels decreased significantly and continuously. Predictive factors for a deterioration in pancreatic function are in order of importance: the extent of obesity, the quality of metabolic control and only last the duration of diabetes. Fortunately, consistent diabetic care can have an impact on the first two.

The KID Study. III: Impact of inpatient rehabilitation on the metabolic control of type I and type II diabetics--a one-year follow-up.

The Kissingen Diabetes Intervention Study (KID) evaluated 1050 diabetic patients of the German Federal Insurance Institution for Salaried Employees (BfA) admitted for inpatient rehabilitation. The data for the prospective longitudinal study (which was collected in a single center) relate to the structure of the patient cohort, socio-economic and psychological factors and the mode of medical management at the time of admission and discharge. Data regarding the same variables was checked by random testing six and twelve months after discharge and used in this part of the study. This cohort of patients is especially interesting for aspects of health policy because it comprises rather young diabetics engaged in highly qualified professional work. Therapy modifications entailing a more intensive insulin regimen were necessary in 20.7% of all type I diabetics. Most of these alterations were maintained over the following 12 months of management by the general practitioner. Improvement of HbA1 levels was related to the number of daily insulin administrations. The results obtained during inpatient treatment in patients on ICT are maintained even one year after their discharge. For type I diabetics, the first training measure especially results in a long-term improvement of the metabolic situation, whereas patients who have already received training several times previously benefit continuously less with increasing repetition of training. After twelve months the intensified insulin therapy of type I diabetics had no further effect on the BMI or the already previously normal serum lipids. In 55.5% of all type II diabetics, the therapy had to be modified. Inpatient rehabilitation resulted in raising the low number of type II diabetics treated just with diet by 5.3%. This proportion was again slightly reduced 12 months later. During inpatient residence the number of overweight type II diabetics treated with drugs was reduced both in the group on oral hypoglycemics and in the group on pre-mixed insulin, according to the weight loss achieved. On the other hand, it was often necessary to intensify the usual insulin regimen twice daily in the group of younger patients with normal body weight. These modifications were maintained twelve months after the stay in hospital for most of these patients. Virtually all type II diabetics on oral hypoglycemics are overweight as a reflection of too early prescriptions of oral hypoglycemics which often neglects the chance of a dietary management only. In this group, therapy modifications were directed towards treatment with diet only and with oral hypoglycemics having an extra-pancreatic action. On metformin, the HbA1 was reduced by 0.3% and the BMI by 0.9 kg/m2 even 12 months later. In the 90% of type II diabetics previously treated with sulphonylureas (almost exclusively glibenclamide), re-modification of therapy from metformin back to the old regimen (16:9%) was especially high. This is probably due to the uncertainty with and general restrictions in the prescription of metformin in the relevant period 1991 to 1995. The results 12 months after inpatient treatment show the small improvement of HbA1 and serum lipids as already seen in other larger interventional studies. The BMI does not change significantly within the relatively short follow-up period. The best long-term results are achieved by a combined therapy with sulphonylurea compounds and metformin. The KID study demonstrates major deficits in intensifying the insulin regimen of type I diabetics and in the individual adaptation to therapy of type II diabetes in Germany, even when younger patients of higher professional status are considered. Interventional inpatient rehabilitation improves their metabolic situation with lasting effect and can compensate deficits in outpatient management by the general practitioner. However, future concepts have to be improved at all levels of diabetic management, with a view to achieving an optimum interaction.

The KID Study. I: Structural baseline characteristics of the Federal Insurance for Salaried Employees' Institution (BfA) diabetic patients in inpatient rehabilitation. Kissingen Diabetes Intervention Study.

% of type I diabetics are not administering insulin according to the intensified conventional therapy schedules, only 16.8% of all type II diabetics are treated with diet only. Type II diabetics are much too often treated with pre-mixed insulins of too high dosage (26.2%) or with oral hypoglycemics (46.2%) of which 90% were sulphonylureas and nearly exclusively glibenclamide. Oral hypoglycemics with extrapancreatic activity or combined therapies were not common among the patients.

The KID Study. II: Socioeconomic baseline characteristics, psycho-social strain, standard of current medical care and education of the Federal Insurance for Salaried Employees' Institution (BfA) diabetic patients in inpatient rehabilitation. Kissingen Diabetes Intervention Study.

The Kissingen Diabetes Intervention Study (KID) evaluated 1050 diabetic patients of the German Federal Insurance for Salaried Employees' Institution (BfA) admitted for inpatient rehabilitation. A single-center prospective, longitudinal study collected data concerning baseline characteristics of patient cohort, socioeconomic factors and mode of intervention at the time of admission, discharge and outcome 6 and 12 months after discharge with consecutively obtained random tests. This cohort of patients is especially interesting for aspects of health policy because it is composed of rather young diabetics engaged in professional work. The data suggest that on the one hand considerably fewer type I diabetics than type II diabetics are married, but that on the other hand constant relationships are equally common in both groups when not considering the marital status. 70% of all diabetics have regular working hours, only 10% of the type II diabetics and negligible 3.9% of the type 1 diabetics work nightshifts. Nevertheless, 29.4% of the type I diabetics and 36.4% of the type II diabetics were unfit for work for at least 4 weeks in the 6 months prior to admission. Only 35.5% of all diabetics see their doctor once or twice monthly. The disease was first diagnosed by the general practitioner in 70% of all cases. Thorough information concerning the disease was provided only in 33.7% of type II diabetics and 26.1% of type I diabetics. 50.6% of type I diabetics and 68.4% of type II diabetics did not receive any education during the all important first year after diagnosis. Most of the diabetic education which had taken place was provided by general hospitals but also by specialized diabetes hospitals and rehabilitation hospitals. 65.6% of all type II diabetics do not monitor urine glucose and those who do so, monitor only once to twice weekly or less. Fortunately 96.3% of all type I diabetics monitor blood glucose, but only 41.0% of them monitor as frequently as is appropriate. 28.3% receive material for monitoring glucose levels only after asking for this. In 32% of the type II diabetics monitoring urine glucose, the general practitioner does not discuss the results with them. Regular controls of glycolysated hemoglobin is part of the diabetic management in 84.4% of all type I diabetics, but carried out in only 34.9% of all type II diabetics, among which the checking of fasting glucose dominates laboratory controls with 50.9%. However, blood lipids are monitored in half of the patients. Huge deficits have been found in the monitoring of urinary albumin excretion in type I diabetics, but especially in type II diabetics. Fear of the future and depression are the predominant strains in everyday life for type I diabetics as well as for type II diabetics. Next most important is the fear of hypoglycemias for type I diabetics, who also feel significantly more restricted in leisure time activities than type II diabetics do. No difference was found between the two groups concerning the demands of treatment. Differences were marked in that more type I than type II diabetics complain of strain in professional life due to their disease, and that a higher proportion of type II diabetics feel impaired by physical complaints (higher incidence of multimorbidity) and consider their relationships more strained by the diabetes than type I diabetics. Surprisingly, problems with accepting the disease and problems in the doctor-patient relationship were of similarly low importance in both groups. We will soon report the changes of the parameters discussed here found after inpatient rehabilitation with intensive diabetic education, promotion of physical activities and psychological measures.

The KID study IV: effects of inpatient rehabilitation on the frequency of glucose self-monitoring, quality of further primary care, on time being unable to work and on everyday psychic strain of type I and type II diabetics--a one-year follow-up. Kissingen Diabetes Intervention Study.

The Kissingen Diabetes Intervention Study (KID) evaluated 1,050 diabetic patients of the German Federal Insurance Institution for Salaried Employees (BfA) admitted for inpatient rehabilitation in a single-center, prospective, longitudinal study which was carried out to collect data concerning the structure of the patient cohort, socioeconomic factors, psychological data and state of medical care by consecutively registered random tests. These results have already been published. We will now report on the outcome 6 and 12 months after inpatient treatment. Consisting of rather young diabetics in higher professional standing, our patient cohort is especially interesting for health policy. The numbers of type I diabetics and of insulin-treated type II diabetics who self-monitor blood glucose levels several times daily significantly increased after inpatient rehabilitation. This situation is maintained 6 and 12 months after discharge. The number of type II diabetics on diet or oral hypoglycemics who do not monitor urinary glucose levels at all, is significantly reduced. The frequency of daily or weekly checks is significantly raised even after 12 months. Due to inpatient diabetic education, self-monitoring of glucose levels plays a more important role in primary care of these patients. 68.5% of all type I and about 60% of all type II diabetics receive test material without problems and are encouraged to continue monitoring. However, about 30% of type I and type II diabetics under primary-care management are still supplied with test material only when especially demanding it. The frequency of consultations in primary care diabetic management remains unchanged after inpatient treatment. The quality of diabetic management in primary care is improved by patient education. Monitoring of HbA1 is significantly increased in type I diabetics and significantly increased in type II diabetics. A similar development is seen in monitoring urinary albumin excretion but here are still deficits. For type II diabetics, the body weight and serum lipids are increasingly controlled main parameters. But in many places and especially in the case of type II diabetics the fasting glucose level is still used as main parameter. Compared with the 6 months prior to inpatient treatment, times when type I and type II diabetics are unable to work are significantly reduced in the 6 months and 12 months after-wards. Evaluating individual profiles of psychosocial strain shows that the more intense confrontation with problems of the disease and demands of the treatment can lead to a poorer quality of life in several categories. This was seen in the categories anxiety, depression, fear of hypoglycemias in the case of type I diabetics, restriction of leisure time activities, relationship with the partner and acceptance of disease. Only in the categories patient-physician relationship and professional strain was an improvement found. These alterations are still demonstrable after 6 and 12 months.

The KID Study VI: diabetic complications and associated diseases in younger type 2 diabetics still performing a profession. Prevalence and correlation with duration of diabetic state, BMI and C-peptide.

A sub-study evaluated 698 younger (54.5 +/- 6.9 years) type 2 diabetics of the KID Study participants to establish the prevalence of diabetic complications and associated diseases and their correlation with body mass index (BMI), duration of disease and to C-peptide levels. Only 19.8% of the type 2 diabetics had a normal weight. In all weight subgroups, the average age of diabetes manifestation were around age 45. In 46.6% of all type 2 diabetics we could already demonstrate microangiopathic complications. Strikingly, 15.9% of the patients already had proliferative retinopathies and 12.6% had albuminuria of more than 1000 mg/dl. 74.7% of our type 2 diabetics presented with the well-known risk cluster of the metabolic syndrome: In every other patient, we found hypertension and/or hyperlipoproteinaemia. Accordingly, the prevalence of the macroangiopathic diabetic complications, coronary artery disease and peripheral vascular disease was 17.8%, which is high for a relatively young population with a mean age of 53.9 years and goes conform with recent literature (Lowel et al., 1999). An increase in BMI correlated significantly with deterioration of HbA1, a decrease in HDL cholesterol, an increase in triglycerides and with a higher prevalence of hypertension. The frequency of nephropathy increase significantly up to a BMI of 30-35 kg/m2. Retinopathies and polyneuropathies were associated with BMI but increased significantly with the duration of the diabetic state. In contrast to microangiopathic diabetic complications, there was already a high prevalence of nephropathy after a comparatively short duration of disease. The prevalence of hyperlipoproteinaemia and hypertension did not depend from the duration of diabetes. These concomitant diseases already were frequent early in the disease and did not increase with the duration of disease. However, there was a strong correlation between increasing hyperlipoproteinaemia and hypertension and higher C-peptide levels. We found no coincidence between C-peptide levels and microangiopathic diabetic complications.

The first memory drum.

For most of the 20th century, the memory drum was the standard American apparatus for memory research. The first memory drum dates from 1887 in the work of G. E. Müller and Frederich Schumann, and an illustration of their device appeared 16 years later. This device apparently was invented to resolve the difficulties created by Ebbinghaus's method. The memory drum was a kymograph used to control the display of learning materials. Cattell used something similar for his dissertation with Wundt, though not for verbal material. From Müller's writings, images of this device and kymographs contemporary to Müller's innovation, characteristics, aspects, and difficulties of the development of this drum are presented in the context of its use to resolve the difficulties created by Ebbinghaus's method. An improved device was offered by instrument makers Diederichs in Göttingen and Zimmermann in Leipzig, both in 1894. Surprisingly, from 1903 Zimmermann offered only the original, unimproved device, mistakenly portraying it as appropriate for paired-associate learning procedures.

[Value of biguanide in therapy of diabetes mellitus]. / Die Stellung der Biguanide in der Therapie des Diabetes mellitus.

BACKGROUND AND OBJECTIVES: Biguanides have been used in treatment of diabetes mellitus for over 30 years now. Due to frequent occurrence of lactic acidosis, particularly in patients with serious contraindications to biguanide therapy and in cases of non-compliance with dosage instructions, buformin and phenformin were taken off the market in most European countries at the end of the seventies. Metformin continued to be allowed, since the risk of lactic acidosis is 20 times less than with phenformin or buformin due to the different pharmacokinetic properties of the substance. Plenty of clinical experience has been gained with metformin, documented in a large number of reliable long-term studies. FINDINGS: Metformin lowers fasting blood glucose levels by an average of 25% (17 to 37%), postprandial blood glucose by up to 44.5% and HbA1c bei 1.5% (0.8 to 3.1%) Metformin reduces raised plasma insulin levels in cases of metabolic syndrome by as much as 30% and reduces the "insulin requirement" of type 2 insulin-treated diabetics by 15 to 32%. It has well documented effects on various rheological parameters. In overweight type 2 diabetics, metformin shows the same level of hypoglycaemic effect as all of the important sulfonylurea derivatives used in Europe. The active mechanism of these derivatives is, however, concentrated solely on reduction of blood glucose. This mechanism does not take into account the remaining risk constellation involved in insulin resistance. Biguanides, similarly to weight reduction, lead to a reduction of hyperinsulinaemia, which is by contrast exacerbated by sulfonylureas and, in particular, exogenous insulin. CONCLUSION: The risk of lactic acidosis can probably be eliminated entirely if dosage instructions and contraindications are observed carefully. The cause of such neglect in 83% of all cases was limited on renal function (serum creatinine > 1.5 mg%). Regarding morbidity and mortality from lactic acidosis, metformin therapy is no riskier than treatment with the sulfonylurea derivative glibenclamide, taking into account the incidence of fatal hypoglycaemias with the latter.

[Mexiletine in treatment of painful diabetic neuropathy]. / Mexiletin in der Behandlung der schmerzhaften diabetischen Neuropathie.

The objective of this double-blind placebo controlled multicenter study was to prove the efficacy of mexiletine in painful diabetic neuropathy. Treatment was provided for in three dosages. For pain measurements a visual analogue scale (VAS) and McGill's verbal rating scale were chosen. 95 patients were included. A global assessment of the VAS showed no differences in treatment. The total evaluation (PRIT = Pain Rating Index Total) of the McGill scale just failed the level of significance. More specific exploratory evaluation of subclasses of the McGill scale, representing different qualities of pain, gave remarkable differences between mexiletine and placebo. According to types of complaints an evaluation showed substantial advantages of the mexiletine treatment with both the VAS and the McGill scale. There is strong evidence that particularly patients with stabbing or burning pain, heat sensations or formication will benefit most by mexiletine therapy. Concerning the dosage, a medium regimen of 450 mg per day seems to be appropriate in this indication. With an increase in dosage the efficacy does not rise proportionally. Mexiletine proved a very safe therapy with negligible side effects at the medium dose range, even less than placebo. There were no cardiovascular side effects. Further investigations should pay more attention to the variety of the complaints and include the quality of life.

[Factor VIII inhibitors in non-hemophiliac patients. A report of cases and therapeutic prospects]. / Inibitori del fattore VIII in pazienti non emofilici. Segnalazione di due casi e prospettive terapeutiche.

Approximately 5-20% of patients with hemophilia A acquire antifactor VIII antibodies during transfusion therapy. These autoantibodies cause serious bleeding and are rarely found in non hemophiliac patients (only a few hundred case reports in the literature). Treatment of this autoimmune condition is quite difficult: corticosteroids, immunosuppressive agents, plasmapheresis and transfusions may be useful. We describe two patients we observed and add some general reflections on therapy.