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[Diabetes mellitus--a complex interaction between heredity and environment].

Genetic factors play an important and probably necessary role, in the development of most forms for diabetes mellitus, but are not the sole cause of the disease. The disease seems to be caused by an interaction between polygenic inheritance and environmental factors. In type I diabetes, more than ten different genetic markers have been found to be associated with the disease. Genes in the HLA-region, on and near the insulin gene, are the most important ones. In the common form of type II diabetes, a series of candidate genes which are code for important steps in insulin secretion or action have been investigated. So far, none have been identified that contribute significantly to the development of the disease in the majority of cases. The most significant breakthrough in research in recent years has been in the study of maturity-onset diabetes of the young (MODY). Until now, mutations in five different genes, which are code for glucokinase and various transcription factors, have been found to be associated with this form of diabetes. Knowledge of the genetic heterogeneity of diabetes has led to a need for a more pathophysiologically correct classification of the disease.

Diabetes Mellitus↗

Dissolved gases as partitioning tracers for determination of hydrogeological parameters.

In this study, dissolved Kr and SF6 gases were used to determine various hydrogeological parameters of laboratory columns under water-saturated and partially saturated conditions as a function of the flow velocity. The dissolved gases behaved conservatively in saturated columns but were significantly retarded in unsaturated conditions as a direct function of the Henry's law constant (KH) and the ratio of column pore spaces filled with air and water (Vg/Vw). Lower aqueous diffusion coefficients for SF6 compared to that for Kr also resulted in significant rate-limited mass transport across gas-water interface. This effect was exacerbated at higher flow velocities as was indicated by the asymmetric shape of breakthrough curves, more so in the case of SF6. A nonequilibrium advective-dispersive transport model accurately described tracer breakthrough and was used to estimate parameters such as final Vg/Vw under partially saturated conditions and partitioning rates. Internally consistent model results were obtained for both dissolved gases despite the wide range in physical properties (e.g., KH and aqueous diffusion coefficients), suggesting that dissolved Kr and SF6 may be used in conjunction to delineate and validate aquifer characteristics simultaneously from a single pulse injection of the tracer.

Geological Phenomena↗

QRS alterations in body surface potential distributions during percutaneous transluminal coronary angioplasty in single-vessel disease.

Body surface QRS potentials were recorded with 63 chest leads in 20 patients with proximal single-vessel disease located on either the left anterior descending coronary artery (n = 10), the right coronary artery (n = 6), or the left circumflex coronary artery (n = 4) before, during, and after percutaneous transluminal coronary angioplasty. In each case, three consecutive inflations of relatively short duration (37 +/- 14 seconds) were carried out. Electrical activity was displayed as unipolar electrograms and body surface potential maps. The total QRS complex duration decreased in 14 of the 20 patients. Focal conduction disturbances were observed in six cases; all six had left anterior descending coronary artery occlusion and two were also accompanied by a clear shortening of the right epicardial breakthrough time. In these two cases, an initial activation loss seemed to be characteristic, whereas in the other four cases, a rather diffuse slowing of intraventricular conduction, especially during the terminal portion of the QRS, could be observed. Individual and group mean isointegral difference body surface potential maps (during-minus-before dilation) were considered valuable for the interpretation of localized changes in intraventricular conduction during percutaneous transluminal coronary angioplasty, and their individual variations could, at least partly, be explained by the presence or absence of collateral circulation. Two different hypotheses are suggested to account for the QRS complex shortening observed during short-term myocardial ischemic injury: (1) coronary artery occlusion delayed activation of the portion of the septal region that is normally activated early during the QRS, and/or (2) coronary artery occlusion increased the speed of propagation within the ventricles. Both of these hypotheses are discussed in light of earlier clinical and experimental results.

Angioplasty, Balloon, Coronary↗

Simultaneous antibiotic levels in "breakthrough" gram-negative rod bacteremia.

Of 237 cases of gram-negative rod bacteremia observed at the UCLA Medical Center during a 12 month period, 52 (22 per cent) occurred while the patient was receiving antibiotics which inhibited the infecting organism by disc diffusion tests. One half of the plasma samples available from 42 such patients with "breakthrough" bacteremia had subinhibitory circulating antibiotic levels when cultures were positive. Sepsis documented within 72 hours of initiation of therapy was usually due to antibiotic-sensitive Esch. coli and was associated with inadequate antibiotic levels; the patient was usually treated with a penicillin or cephalosporin. The source of bacteremia was most frequently the urinary tract or the biliary tree. In contrast, sepsis occurring more than 72 hours after the administration of antibiotics was frequently caused by multiple antibiotic-resistant Esch. coli in patients treated with gentamicin in adequate dosage and was associated with leukopenia or undrained purulent collections. Therapy ultimately failed in 20 cases (48 per cent): in early "breakthrough" bacteremia, failure was associated with subinhibitory antibiotic levels, and in late "breakthrough" bacteremias with inadequate drainage or impaired host defenses.

Anti-Bacterial Agents↗

Exacerbation of mania secondary to right temporal lobe astrocytoma in a bipolar patient previously stabilized on valproate.

OBJECTIVES: To investigate breakthrough mania secondary to a right temporal lobe neoplasm in a bipolar patient previously stabilized on sodium divalproex. BACKGROUND: Right hemispheric brain tumors involving the orbitofrontal or basotemporal cortex are a rare cause of secondary mania. In such cases, early neurologic signs may be difficult to distinguish from bipolar symptoms. Breakthrough mania secondary to brain neoplasm in a bipolar patient stabilized on medication is an extremely rare phenomena which has not been previously reported. METHOD: The clinical course of a bipolar subject stabilized on valproate who developed mania secondary to a right temporal lobe astrocytoma is described. Serial brain magnetic resonance imaging (MRI), baseline electroencephalogram (EEG), and neuropsychiatric evaluations were used to examine the relationship between the patient's brain mass and behavioral disturbances. RESULTS: Symptoms were those that accompanied prior episodes of mania. In addition, signs of temporal lobe dysfunction were evident including periods of detachment, déjà vu experiences, and olfactory hallucinations. In the context of mania, depersonalization was initially attributed to bipolar symptoms. Only several months later, when olfactory hallucinations and alterations in consciousness became evident, was a temporal lobe lesion suspected. Neuropsychiatric abnormalities responded to a combination of surgical intervention, radiation therapy, and topiramate, however the tumor was advanced and invasive at diagnosis resulting in a poor prognosis. CONCLUSIONS: This case suggests that clinicians examining unexplained cases of breakthrough mania should be vigilant for early signs of temporal lobe dysfunction, which could aid in detecting treatable lesions.

Anticonvulsants↗

Bacterial biofilm formation in the urinary bladder of spinal cord injured patients.

Ten spinal cord injured patients aged 8 to 55 years (mean 32) were followed for up to 2 months after admission to a rehabilitation setting from an acute care hospital. Urinary fluid and bladder epithelial cells were collected weekly by intermittent catheterization and examined for bacterial colonization. Six patients had no history of urinary tract infection upon admission, likely due to the antimicrobial coverage given during acute care. All the patients subsequently became colonized with uropathogens at some time during the study period. Bacterial biofilms were found in 73% of the samples (73% Gram negative organisms, 27% Gram positive), with mean pathogenic adhesion counts of 29 organisms per bladder cell. In 16% of cases, bladder biofilms were found when urine culture was negative. Bacterial biofilms were also evident during antimicrobial therapy in 10 of 12 samples tested and urine cultures showed breakthrough infections in 50% of cases. Two asymptomatic patients were colonized with Klebsiella pneumoniae and Pseudomonas aeruginosa and were dismissed without requiring therapy. Clearly, bacterial biofilms can exist on bladder epithelia, without being detected in urine samples and without giving rise to symptoms. The extent to which they occur and damage the host remains to be determined, as does the answer to the question, should these patients be treated?

Adult↗

Successful treatment of the normal perfusion pressure breakthrough syndrome.

Massive, multifocal bleeding after the technically successful removal of a cerebral arteriovenous malformation (AVM) represents a frightening and usually catastrophic complication. This phenomenon, termed normal perfusion pressure breakthrough by Spetzler et al., is caused by the diversion of blood flow from the AVM into adjacent, maximally dilated, and nonautoregulating small vessels. We recently encountered three cases of cerebral AVM that exhibited breakthrough bleeding immediately after an apparently successful operation. In all cases, the surgeon was unable to control the resultant hemorrhage by standard microsurgical techniques. High dose barbiturate anesthesia, combined with blood pressure reduction to the lower levels of the normal cerebral perfusion curve, was then initiated in each case. Controlled hyperventilation, steroids, and osmotic dehydrating agents were also used to control intracranial pressure elevation. After maintenance of this regimen for several days, the patients were returned to the operating room for hematoma evacuation. At this time, bleeding was controlled easily and breakthrough did not occur. Although this regimen requires intensive anesthetic, pulmonary, and cerebral monitoring, it successfully salvaged all three patients. Two made immediate, remarkable recoveries, and the third patient is slowly improving. This protocol therefore seems promising for the management of the massive, uncontrollable cerebral swelling or bleeding that may occur as a consequence of AVM removal.

Adult↗

Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals. Multicenter AIDS Cohort Study.

Effective HIV-1 therapies may directly or indirectly impact the development of AIDS-associated malignancies. Using data from the Multicenter AIDS Cohort Study, a longitudinal cohort study of the natural history of HIV-1 infection among homosexual men, the incidence rates of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) over calendar time were determined for the 1813 HIV-1-seropositive men enrolled in 1984 through 1985. Poisson regression models were used to identify statistically significant temporal trends. Nested case control studies were used to assess whether recent cases of these malignancies represented treatment breakthroughs. The incidence of KS as a presenting AIDS illness significantly (p = .003) declined from 25.6 cases per 1000 person-years (95% confidence interval [CI], 21.8-29.9) in the early 1990s to an average incidence of 7.5 per 1000 person-years (95% CI, 3.4-16.7) in 1996 through 1997. In contrast, the incidence of NHL has continued to increase significantly (p < .001) at a rate of 21% per year since 1985, although a possible recent decrease is suggested. None of the recent KS cases and only 1 of 8 NHL cases had used the potent antiretroviral therapies, compared with >70 percent of the HIV-1-seropositive men who were free of malignancies and observed over the same time period. These results may be due to an indirect protection against developing KS by the boosting of the immune system by antiretroviral therapies. However, it is important to clarify the direct therapeutic effect on the pathogenic disease mechanism of human herpesvirus type 8 (HHV-8), the agent postulated to be important in the causal pathway of KS. The absence of a similar effect on NHL may be due to a lack of effect on its pathogenesis or because potent antiretroviral therapies need to be administered early in the disease process and the cases that have occurred represent outcomes following a long latency period. With additional follow-up, an impact on NHL may yet be observed.

AIDS-Related Opportunistic Infections↗

Chickenpox outbreak in a highly vaccinated school population.

OBJECTIVE: We investigated a chickenpox outbreak that started in an Oregon elementary school in October 2001, after public schools began phasing in a varicella vaccination requirement for enrollment. We sought to determine the rate of varicella vaccination and effectiveness and risk factors for breakthrough disease. METHODS: A chickenpox case was defined as an acute maculopapulovesicular rash without other explanation occurring from October 30, 2001 through January 27, 2002 in a student without a prior history of chickenpox. We reviewed varicella vaccination records and history of prior chickenpox, and we calculated vaccine effectiveness. We evaluated the effects of age, gender, age at vaccination, and time since vaccination on risk of breakthrough disease (ie, chickenpox occurring >42 days after vaccination). RESULTS: Of 422 students, 218 (52%) had no prior chickenpox. Of these, 211 (97%) had been vaccinated before the outbreak. Twenty-one cases occurred in 9 of 16 classrooms. In these 9 classrooms, 18 of 152 (12%) vaccinated students developed chickenpox, compared with 3 of 7 (43%) unvaccinated students. Vaccine effectiveness was 72% (95% confidence interval: 3%-87%). Students vaccinated >5 years before the outbreak were 6.7 times (95% confidence interval: 2.2-22.9) as likely to develop breakthrough disease as those vaccinated </=5 years before the outbreak (15 of 65 [23%] vs 3 of 87 [3%]). CONCLUSIONS: A chickenpox outbreak occurred in a school in which 97% of students without a prior history of chickenpox were vaccinated. Students vaccinated >5 years before the outbreak were at risk for breakthrough disease. Booster vaccination may deserve additional consideration.

Chickenpox↗

[Evaluation of cerebral hemodynamics by 123I-IMP in cerebral AVMs before and after operation by using SPECT].

To evaluate cerebral hemodynamics by N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP) preoperative and postoperative (after 1 day, and after 7-10 days) regional cerebral blood flow scan, 6 arteriovenous malformations (AVMs) which performed total removal operations were studied by using a ring type SPECT "HEADTOME". We performed the dynamic scan just after the intravenous injection of 222 MBq (6 mCi) of 123I-IMP, then the static scan 20 minutes after the intravenous injection. In preoperative dynamic scans of all cases, only the first frame image showed the increased activity on the nidus probably because of the blood pool. Preoperative static scans of all cases showed the remarkable decreased activity on the nidus, and decreased activity surrounding the nidus probably because of the peripheral steal phenomenon. In postoperative scan of the next day, 4 out of 6 cases showed the transient decreased peripheral steal, particularly 2 out of those 4 cases showed the transient hyperperfusion probably because of the normal perfusion pressure breakthrough (NPPB). And, 2 out of 6 cases showed transient peripheral low perfusion on much larger area than those of the preoperative scans probably because of the focal brain damages and edemas. We conclude that 123I-IMP SPECT on AVM is very useful to decide the indication of the removal operation, and to estimate the postoperative risk, and to evaluate the preoperative and postoperative cerebral hemodynamic changes in the peripheral area of AVM.

Adolescent↗

Detection of the breakthrough of organic solvent vapors on an activated carbon adsorption column using a gas detecting reagent.

A new adsorption device which is able to detect the breakthrough of organic solvent vapors was developed using a detecting reagent which is packed in a gas detector tube. The organic vapor which leaks from an activated carbon adsorption column reacts with the detecting reagent. The breakthrough is detected by the stain of the reagent. When the humidity of test air was zero, the reagent was stained sharply before the breakthrough was observed. However, in the case of using humid air, the color of the detecting reagent did not clearly change, even after the breakthrough had progressed considerably.

Absorption↗

NOM-facilitated transport of metal ions in aquifers: importance of complex-dissociation kinetics and colloid formation.

The transport of metal ions (Al, Fe, Zn, Pb) complexed by natural organic matter (NOM) was investigated by column experiments. Direct breakthrough of metal-NOM complexes was observed after elution of one bed volume for Al, Fe, and Pb, but not for Zn. This observation cannot be understood assuming local thermodynamic equilibrium in the columns. Hence, a model was developed, taking into account the kinetics of the interactions of metal ions with NOM and the solid phase. Of all possible reactions during passage through the column, the dissociation of the metal-NOM complexes was assumed to be the rate-determining step. Dissociation-rate constants were determined by cation-exchange experiments with a non-NOM-adsorbing cation-exchange resin (Chelex-100). These rate constants were used to predict the migration of metal-NOM complexes in the column experiments. Experimental and modeling results were in good agreement for the bivalent metal ions. Also, the model well predicted the pH dependence of breakthrough of trivalent metal ions and the differences between Al and Fe breakthrough on a qualitative basis. This leads to the conclusion that the dissociation kinetics of metal-NOM complexes is an essential parameter for the estimation of NOM-facilitated metal transport. However, for the trivalent metals, Al and Fe, the model overestimated the direct breakthrough, thus giving a worst case prediction of metal transport. With the help of coupling size-exclusion chromatography to inductively coupled plasma-mass spectrometry, the formation of Al-hydroxide and Fe-hydroxide colloids in addition to NOM complexes was detected. These colloids, which were not considered in the model, were partially filtered off in the column, thus leading to overestimation of metal breakthrough.

Chromatography, Gel↗

Treatment of chronic hepatitis C with recombinant human interferon-alpha 2a: results of a randomized controlled clinical trial.

Sixty consecutive patients with chronic hepatitis C were included in a randomized controlled trial of recombinant human interferon-alpha 2a vs. no treatment. Treated patients received tapering doses of interferon thrice weekly for 1 yr. Twenty treated cases (66.7%) normalized serum aminotransferase levels within the first 4 mo of treatment, but reactivation or breakthrough frequently occurred afterward (20% in both cases). Only one of the untreated patients showed spontaneous normalization of serum aminotransferase levels. Liver histology did not improve in patients without a biochemical response or with breakthrough during therapy, whereas it did not worsen in long-term responders and reactivating patients. Lack of response does not appear to be related to serum interferon antibodies, although their early appearance is more frequent in patients who showed reactivation later on. No biochemical parameter was found to be predictive for positive response to treatment. Antibody to c100 became negative in 62.5% of long-term responders, whereas no change was recorded in other treated patients or controls. Reactivation and breakthrough often occur during treatment, and further studies are needed to determine the most effective schedule (dose and time) of interferon treatment. Loss of c100 antibody during therapy may be a marker of long-term maintenance of response to interferon therapy.

Adult↗

Recognition of the epicardial breakthrough on body surface isopotential maps: influence of the inter-electrode distance on the patterns reflecting the epicardial breakthrough.

The epicardial breakthrough can be recognized from the localized depression of the body surface potential, which is characterized by a localized bend of the equipotential lines or a send-minimum on isopotential maps. Recognition of epicardial breakthrough with isopotential maps enables us to diagnose location of the block site of the bundle branch blocks more precisely than by ECG or VCG. However, the optimum inter-electrode distance for detection of such a localized potential has not been determined. In the present study, influence of the inter-electrode distance on the characteristic patterns reflecting the epicardial breakthrough was studied on 16 healthy persons using 9 x 9 electrode arrays with inter-electrode distance of 1.25 cm, 5 x 5 with 2.5 cm, and 3 x 3 with 5 cm. Breakthrough was recognized in 15 out of 16 cases (94%) on maps recorded with electrode arrays with inter-electrode distance of 1.25 and 2.5 cm. However, detectability of the breakthrough was reduced to 10 out of 16 cases (63%) with electrode array having inter-electrode distance of 5 cm. In conclusion, it is preferable to use an electrode array with an inter-electrode distance of no more than 2.5 cm for the purpose of breakthrough recognition.

Adult↗

Cycle threshold values and SARS-CoV-2 variant associations with breakthrough infections: a retrospective study in Accra, Ghana.

BACKGROUND: Breakthrough infections are defined as SARS-CoV-2 infections occurring&#x2009;&#x2265;&#x2009;14 days after completing the primary COVID-19 vaccination series and remain a public health challenge, particularly in regions where immune-evasive variants are circulating. However, data on their virological and clinical profiles in low-resource settings are limited. METHODS: This retrospective study was conducted from July to December 2022 in Accra, Ghana, among individuals testing positive for SARS-CoV-2. Real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) was performed using the Allplex&#x2122; 2019-nCoV Assay. Cycle threshold (Ct) values for the nucleocapsid (N), RNA-dependent RNA polymerase (RdRP), and envelope (E) genes, categorised as <&#x2009;25, 25&#x2013;30, or >&#x2009;30. Variant identification targeted Alpha, Delta, and Omicron mutations using mutation-specific RT-PCR. Logistic regression was used to assess associations between vaccination status and demographic, clinical, and virological factors. RESULTS: Of the 268 samples analysed, 81 tested positive; 43.20% [n&#x2009;=&#x2009;35] were vaccinated individuals. Median Ct-values for the N [27.13, IQR: 21.59&#x2013;31.96] and E [24.57, IQR: 19.43&#x2013;29.43] genes were significantly higher among vaccinated cases, indicating lower viral loads. Breakthrough infections were strongly associated with the Omicron variant [aOR&#x2009;=&#x2009;4.38, p&#x2009;=&#x2009;0.034]. Diarrhoea [aOR&#x2009;=&#x2009;9.67, p&#x2009;=&#x2009;0.022], sore throat [aOR&#x2009;=&#x2009;8.99, p&#x2009;=&#x2009;0.038], headache [aOR&#x2009;=&#x2009;10.156, p&#x2009;=&#x2009;0.039] and chills [aOR&#x2009;=&#x2009;3.316, p&#x2009;=&#x2009;0.046] were mostly associated with breakthrough infections. Ct-values of 25&#x2013;30 [aOR&#x2009;=&#x2009;11.33, p&#x2009;=&#x2009;0.012] and >&#x2009;30 [aOR&#x2009;=&#x2009;4.01, p&#x2009;=&#x2009;0.047] were significantly associated with breakthrough infection compared to Ct&#x2009;<&#x2009;25 in breakthrough infections. CONCLUSION: Vaccinated individuals with SARS-CoV-2 infection had lower viral loads and were more likely to be infected with the Omicron variant. These findings reinforce the role of vaccination in reducing viral load and support the adoption of practical surveillance strategies, such as Ct value-based surveillance and variant screening in low middle-income countries facing similar constraints in genomic capacity and vaccine deployment.

Humans↗

Achieving breakthrough outcomes: measurable ROI.

You're a case manager. Your boss is talking return on investment (ROI). Your patients don't want to be numbers on a spreadsheet. What does it take to be a hero to both the boss and the patient? Case managers frequently try to argue that great gains in quality of life for the patient are so valuable that management ought to ease up on case managers when talking about budget and returns. An experienced quality professional might respond, "Good luck."

Anthropology, Cultural↗

Use of myocardial imaging agents for tumour diagnosis--a success story?

The search for new radiopharmaceuticals for tumour diagnosis usually proceeds on the basis of rational concepts drawing on the latest advances in molecular biology. Using this approach, radioactive peptide hormones, antibodies and oligonucleotides have been developed that are used increasingly in nuclear medicine for diagnostic and therapeutic purposes. This article, however, focusses on a group of radiopharmaceuticals whose use in tumour diagnosis was not the outcome of a methodical development programme but rather the result of a chance discovery. These radiopharmaceuticals, thallium-201 and technetium-99m labelled 2-methoxyisobutylisonitrile (MIBI), tetrofosmin and furifosmin, were first developed through extensive research efforts for cardiac imaging, but during their worldwide application for myocardial scintigraphy they were accidentally found to accumulate in tumours. Intensive studies were then begun on cell cultures in an attempt to discover the cause of their uptake into tumours. The aim was to compare the effectiveness of the radiopharmaceuticals for tumour diagnosis in a range of indications and to investigate the various mechanisms by which they are taken up into tumours. While the more favourable radiophysical properties of 99mTc-MIBI render it superior to 201Tl for many diagnostic purposes, neither 99mTc-tetrofosmin nor 99mTc-furifosmin has yet proved suitable for clinical routine examinations, although the former has found limited application. In the case of 99mTc complexes, the breakthrough came with the experimental finding that these substances are substrates of P-glycoprotein, a product of the human multidrug resistance gene (MDR1). The concentration of 99mTc complexes in tumour cells is a function of a passive, membrane potential-dependent influx into and a P-glycoprotein-controlled efflux out of the tumour cell. Preliminary studies suggest that in vivo detection of MDR may even be possible. There is also evidence that the P-glycoprotein-mediated transport system can be blocked competitively. However, it will be some time before a system can be developed for detection of MDR on a routine basis.

Drug Resistance, Neoplasm↗