Hepatic encephalopathy. Application of visual evoked responses to test hypotheses of its pathogenesis in rats

A previous study of the patterns of visual evoked responses (VERs) in rats was interpreted as providing support for the synergistic neurotoxins hypothesis of the pathogenesis of hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF). In contrast, other studies of the patterns of VERs in rabbits with different encephalopathies were interpreted as providing support for the concept that increased GABA-ergic tone may contribute to the neural inhibition of HE due to FHF. To attempt to resolve the discordant findings in these studies, additional studies of VERs have been undertaken in rats. To induce increased tissue levels of ammonia, mercaptans and fatty acids which are found in HE due to FHF, carefully predetermined doses of urease, dimethyldisulphide and octanoic acid were administered. The (pre-seizure) encephalopathy induced by these three agents was associated with abnormalities of the VER waveform that were fundamentally different from the abnormalities of the VER waveform associated with HE due to thioacetamide-induced FHF. However, the VER waveform in this model of HE due to FHF resembled closely that associated with pentobarbital-induced encephalopathy. These findings are in satisfactory agreement with those in the previous analogous studies in rabbits. They do not provide support for the synergistic neurotoxins hypothesis of the pathogenesis of HE, but are entirely consistent with increased GABA-ergic tone contributing to the neural inhibition of HE due to FHF.     

Hepatocellular Carcinoma: the Impact of NAFLD

The burden of chronic liver diseases including hepatocellular carcinoma (HCC) due to non-alcoholic steatohepatitis (NASH) and metabolic syndrome (MS) is increasing worldwide. Moreover, MS and its components act as co-factors in HCC development in patients with other chronic liver diseases due to high alcohol intake or hepatitis B or C infection. Patients with NASH-related HCC are frequently older; their tumors are more frequently diagnosed in non-cirrhotic livers and at an advanced stage compared to HCC due to other etiologies. Patients with MS appear also to be at risk of post-operative complications after liver resection and transplantation. However, after adjustment for tumor burden and severity of the underlying liver disease, long-term outcomes appear to be similar for NASH-related HCC and HCC due to other etiologies. Research on preventive strategies, screening programs for patients with NASH without cirrhosis but at high risk of HCC development, and new therapeutic strategies are warranted in order to respond to this emerging menace.     

Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases

We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/β-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/β- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.     

The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly

We interviewed 315 consecutive elderly patients admitted to an acute care hospital to determine the percentage of elderly hospital admissions due to noncompliance with medication regimens or adverse drug reactions, their causes, consequences, and predictors. Eighty-nine of the elderly admissions (28.2%) were drug related, 36 due to noncompliance (11.4%), and 53 due to adverse drug reactions (16.8%). One hundred three patients had a history of noncompliance (32.7%). Factors statistically associated with a higher risk of hospitalization due to noncompliance were poor recall of medication regimen, seeing numerous physicians, female, medium income category, use of numerous medications, and having the opinion that medications are expensive. Factors associated with an increased risk of an admission due to an adverse drug reaction were use of numerous different medications, higher medication costs, receiving Medicaid, and not receiving any home services. In conclusion, many elderly admissions are drug related; noncompliance accounting for a substantial fraction of these. Elders at high risk of being noncompliant are identifiable using a variety of criteria. Economic factors were important in predicting admissions due to noncompliance as well as adverse drug reactions.     

Burden of increased blood glucose due to modifiable risk factors among men in India

Background and aimsWorldwide, many diabetes cases are occurring mainly due to lifestyle risk factors. Hence, to quantify and compare the attributable burden of key modifiable risk factors associated with increased Blood Glucose (BG) among Indian states and districts.MethodsThe study used the National Family Health Survey (2015–16) data to estimate Population Attributable Risk (PAR) for increased BG (>140 mg/dl) among men aged 15–54 years in 640 districts of 36 States/Union Territories (UTs), India. We have considered three key modifiable factors such as high Body Mass Index (BMI), use of tobacco and alcohol. Population Attributable Risk techniques were employed to address the attributable burden of increased blood glucose due to modifiable risk factors.ResultsSubstantial variations were found in the burden of increased BG due to high BMI, alcohol and tobacco use in India. The overall burden of increased BG due to high BMI, tobacco and alcohol in India was 28.5%, 2.1% and 6.4%, respectively. Regional variations in BG were found in high BMI, tobacco and alcohol consumption groups. The high burden of increased BG related to the above key modifiable risk factors mostly seen in North-Eastern’ districts due to alcohol, Southern and Northern’ districts was due to high BMI. However, the higher burden due to tobacco was reported in Central, Eastern and North-Eastern’ districts.ConclusionThree modifiable risk factors are contributing significantly to increased BG among men. Since there are regional differences in their contributions, state/district, specific targeted interventions may be necessary to control increased BG among men in India.     

Causes of death in atrial fibrillation: Challenges and opportunities

Atrial fibrillation (AF) is an age-related arrhythmia associated with several co-morbidities and significant mortality. Most AF patients are in need of anticoagulation due to increased risk of stroke. Despite anticoagulation, AF patients still have a significant risk of death (about 5%/y). Approximately half of deaths in AF are due to heart-related causes (i.e., sudden death, heart failure, and myocardial infarction), one-third of deaths are due to non-vascular causes (i.e., cancer, respiratory diseases, and infections) and the remaining AF patients die from stroke or hemorrhage (about 6% each), or other causes. This review describes current situations related to causes of death in AF, the challenges in the management of AF (e.g., frequent presence of cardiovascular risk factors and co-morbidities, physicians adherence to clinical guidelines and patients adherence to cardiovascular medications in AF) as well as the opportunities for intervention.     

Transformation-Induced Relaxation and Stress Recovery of TiNi Shape Memory Alloy

The transformation-induced stress relaxation and stress recovery of TiNi shape memory alloy (SMA) in stress-controlled subloop loading were investigated based on the local variation in temperature and transformation band on the surface of the tape in the tension test. The results obtained are summarized as follows. (1) In the loading process, temperature increases due to the exothermic martensitic transformation (MT) until the holding strain and thereafter temperature decreases while holding the strain constant, resulting in stress relaxation due to the MT; (2) In the unloading process, temperature decreases due to the endothermic reverse transformation until the holding strain and thereafter temperature increases while holding the strain constant, resulting in stress recovery due to the reverse transformation; (3) Stress varies markedly in the initial stage followed by gradual change while holding the strain constant; (4) If the stress rate is high until the holding strain in the loading and unloading processes, both stress relaxation and stress recovery are large; (5) It is important to take into account this behavior in the design of SMA elements, since the force of SMA elements varies even if the atmospheric temperature is kept constant.     

Structural alterations of nerve during cuff compression.

Whether compression nerve injury is due to ischemia, direct mechanical injury, or both remains unsettled. To assess structural changes of nerve during compression, peroneal nerves of rats were compressed at various pressures for different times, and the structural alterations were stopped by simultaneous in situ and perfusion fixation. The structural changes observed during a few minutes of compression cannot be explained by ischemic injury because the pathologic alterations characteristic of ischemia take many hours to develop and in any case are different from the ones found here. The pressure- and time-related structural changes observed in the present study under the cuff were (i) decrease in fascicular area and increase in fiber density due to expression of endoneurial fluid; (ii) compression and expression of axoplasm, sometimes to the point of fiber transection; (iii) lengthening of internodes; and (iv) obscuration of nodes of Ranvier due to cleavage and displacement of myelin and overlapping of nodes by displaced loops of myelin. At the edges of the cuff the changes were (i) increase of fascicular area probably from expressed endoneurial fluid; (ii) widening of nodal gaps, perhaps mainly from translocated axonal fluid; and (iii) disordered structure of axoplasm. We suggest that the process of paranodal demyelination and axonal transection are linked, occur during the act of compression, and are due to shear forces. The initial event is expression of endoneurial fluid, followed by compression and expression of axoplasm and cleavage and displacement of layers of myelin. Conceivably, with prolonged cuff compression ischemic injury might be found to be superimposed on mechanical injury.     

Auscultatory and oscillometric methods of ambulatory blood pressure monitoring, advantages and limits: a technical point of view

Two methods of indirect blood pressure (BP) measurement are currently used for ambulatory blood pressure measurement (ABPM): the auscultatory and oscillometric methods. The auscultatory method is based on the detection of Korotkoff sounds issued from the acoustic transudcer signal. Its main advantages are (1) similarities with usual clinical measurement of BP; and (2) accurate detection of systolic and diastolic pressures on the appearance and disappearance of sounds. The main disadvantages of this method are (1) artefacts due to movements; and (2) difficulties in signal analysis due to physiological variations of the Korotkoff sound patterns or poor signals. Difficulties can be overcome by appropriate signal processing (K2 recognition), noise rejection and/or ECG gating. This may allow relatively accurate BP measurement during mild exercise. With the oscillometric method, air volume variations in the cuff are detected during deflation. The maximum oscillation is related to the mean arterial pressure. The systolic and diastolic BP are determined by an algorithmic interpretation of the shape of oscillometric amplitudes as well as the heart rate. The main advantages are (1) possibility of BP measurement when the Korotkoff signal is poor; (2) measurement of the mean arterial BP; and (3) no need of a microphonic sensor. The main disadvantages are (1) some oscillometric curves are difficult to read accurately; (2) oscillometry is very sensitive to movements due to the bandwidth of the signals, so the arm must be immobile; and (3) the accuracy of the systolic and diastolic BP depends on the algorithm used. These two methods are complementary and should ideally be associated in the same device.     

Management of pneumothorax

Pneumothoraces are classified as spontaneous, traumatic, and iatrogenic. Spontaneous pneumothoraces (SPs) occur without recognized lung disease [primary spontaneous pneumothoraces (PSPs)] or due to an underlying lung disease [secondary spontaneous pneumothoraces (SSPs)]. Treatment of PSPs and SSPs has been heterogeneous in the United States. This heterogeneity in management is likely due in part to the fact that the American College of Chest Physicians guidelines and the British Thoracic Society guidelines differ on some management recommendations, including recommendations that pertain to simple aspiration. Traumatic pneumothoraces due to penetrating or nonpenetrating (blunt) trauma usually require the placement of a larger-bore chest tube. Iatrogenic pneumothoraces, most commonly due to transthoracic needle aspiration, may be treated in carefully selected patients with observation. The presence of underlying emphysema in the setting of an iatrogenic pneumothorax usually mandates placement of a drainage catheter.     

Pathogenesis of diabetic neuropathies

There are two types of diabetic neuropathy: on the one hand, mononeuritis and, on the other hand, the symmetric polyneuropathy with a glove and stocking distribution and autonomic polyneuropathy. Mononeuritis (or mononeuritis multiplex) seems to be the result of ischaemia due to intrinsic or extrinsic (altered coagulability) vascular disease. Polyneuropathy is probably due to metabolic factors related to chronic hyperglycaemia: abnormal nerve energy metabolism, impaired axonal transport, increased activity of the sorbitol pathway, non-enzymatic nerve protein glucosylation and abnormal myo-inositol metabolism. The respective roles of these different factors in the pathogenesis of polyneuropathy are discussed.     

The disease burden of hepatitis B in Uzbekistan

OBJECTIVE: To describe the burden of hepatitis B illness in Uzbekistan by means of model-based estimates. METHODS: A mathematical simulation model was developed to mimic the disease evolution of hepatitis B and calculate the size and age of specific HBV patient groups, defined according to the severity of their illness. RESULTS: The calculations indicate that of 678000 neonates in Uzbekistan, 159185 (235 per 1000) would incur an HBV infection at some time during their lives. About 55095 persons (81 per 1000) would become chronic carriers of hepatitis B and 6307 persons (9.3 per 1000) are expected to die due to hepatitis B before they would die from another cause. In the overall population, we calculated that about 3074 Uzbeki die each year from the consequences of hepatitis B. Only 3.2% of these premature HBV-deaths are due to acute hepatitis B, whereas 96.8% are due to chronic hepatitis B. It was calculated that 2.1% of all deaths (or 1 in 47 deaths), and nearly 25% of deaths (or one in four deaths) between 30 and 40 years of age in Uzbekistan are due to hepatitis B. Vaccination seems easily defensible on the basis of rudimentary but very conservative cost-effectiveness calculations ($84 per carrier prevented; $735 per death prevented and $22 per life-year gained). CONCLUSION: Hepatitis B represents a huge health problem in Uzbekistan, especially in young adults. The potential for prevention by vaccination seems very high, but demands a long-term vision if chronic hepatitis, in particular, is to be reduced. Routine hepatitis B vaccination was found to be a relatively cost-effective intervention in Uzbekistan.     

Nonalcoholic steatohepatitis and hepatocellular carcinoma: Beyond the boundaries of the liver

The burden of non-alcoholic steatohepatitis (NASH) related hepatocellular carcinoma (HCC) is drawing attention due to the emerging epidemic of obesity and metabolic syndrome and is expected to increase in the near future. Antidiabetic medications, air pollutants, and newer genetic mutations are latest concerns as risk factors for HCC development in patients with NASH. Although molecular signatures are very accurate, they are not cost-effective and cannot be applied in larger population due to logistic issues. We need multicentric longitudinal studies including diverse geographical areas to evaluate the complex interplay of different risk factors and genetics in these patients.     

A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization

Reactivation of hepatitis B virus (HBV) during chemotherapy is well documented. However, there are limited data on this complication in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemotherapy. The aim of this study was to evaluate the efficacy of preemptive lamivudine therapy in reducing hepatitis due to HBV reactivation in patients with HCC undergoing transarterial chemo-lipiodolization (TACL) and to seek predictors of this event. A total of 73 consecutive HCC patients undergoing TACL using epirubicin 50 mg/m2 and cisplatin 60 mg/m2 at monthly intervals were prospectively and randomly assigned to receive lamivudine 100 mg daily from the start of TACL (preemptive group) or not (control group). During the study, 11 (29.7%) of 37 patients in the control group and 1 (2.8%) of 36 patients in the preemptive group developed hepatitis due to HBV reactivation (P = .002). In addition, there were significantly more incidences of overall hepatitis (P = .021) and severe grade of hepatitis (P = .035) in the control group. With multivariate Cox regression model, a baseline HBV DNA level of more than 10(4) copies/mL was the only independent predictor of hepatitis due to HBV reactivation during chemo-lipiodolization (P = .046). In conclusion, preemptive lamivudine therapy demonstrated excellent efficacy in reducing hepatitis due to HBV reactivation and hepatic morbidity during TACL. Preemptive therapy should be considered in HCC patients with an HBV DNA level of more than 10(4) copies/mL. Further studies are needed to confirm the value of this approach in patients with low-level viremia.     

Clinical significance of a test for slime production in ventriculoperitoneal shunt infections caused by coagulase-negative staphylococci

Coagulase-negative staphylococci (CNST) are the most-common cause of ventriculoperitoneal shunt infections. Some of these strains produce a slime-like substance. We reviewed 19 episodes of ventriculoperitoneal shunt infections due to CNST in 17 patients. Eleven episodes of infection were caused by slime-producing CNST and eight by non-slime-producing CNST. Shunt obstruction and abdominal pain occurred more frequently when infectious episodes were due to slime-producing CNST than to non-slime-producing CNST (P less than .05). Despite appropriate antimicrobial therapy, the mean duration of fever was longer and the failure to eradicate the infecting organisms was more frequent when the infectious episodes were due to slime-producing CNST than to non-slime-producing CNST (P less than .025). Discriminate function analysis found, however, that only failure to eradicate the infecting organism (by antimicrobial therapy) occurred more frequently in infectious episodes due to slime-producing CNST than to non-slime-producing CNST (P = .01).     

Proton Nuclear Magnetic Resonance Studies of Ribonuclease A in H2O

A resonance (designated a) due to an exchangeable proton titrates (pK(a) = 6.1) between 11.5 and 13 ppm in the nuclear magnetic resonance spectrum of RNase A-0.2 M NaCl in H(2)O at 20 degrees . Comparison with models has permitted assignment to a ring-nitrogen proton of histidine in slow exchange with solvent H(2)O. The pH and temperature-dependent line-width changes of resonance a are analyzed in terms of an exchange between histidine and protonated histidine, without the necessity to invoke any exchange processes associated with protein conformational changes. Several other resonances due to exchangeable protons are observed between 10 and 15 ppm in the nuclear magnetic resonance spectrum of RNase A in H(2)O.     

Transient left septal fascicular block and left anterior fascicular block as a consequence of proximal subocclusion of the left anterior descending coronary artery

The association of left anterior fascicular block (LAFB) with left septal fascicular block (LSFB) characterizes a left bifascicular block subtype rarely described in the literature, probably due to the fact that most researchers are not aware of the existence of the left septal fascicle. We describe a case with this transient intraventricular dromotropic disturbance due to left anterior descending coronary artery subocclusion.     

Pathogenesis of secondary hyperparathyroidism and renal bone disease

Patients with chronic renal disease (CKD)almost always develop secondary hyperparathyroidism (SHPT) due to hypocalcemia, phosphate retention, and abnormalities in vitamin D (VD) metabolism. Concomitant decreases in VD receptor and calcium sensing receptor in the parathyroid glands render them more resistant to the action of VD and calcium, and accelerate parathyroid cell growth. Several types of bone diseases are known to occur in CKD patients. Excessive secretion of parathyroid hormone (PTH) due to SHPT causes high-turnover bone disease, called osteitis fibrosa. Among low-turnover bone disease (LTBD), osteomalacia which is characterized by calcification defect is often complicated with VD deficiency and/or aluminum accumulation. Recently, frequency of adynamic bone disease caused by PTH suppression, another type of LTBD, is increasing probably due to calcium salts as phosphate binder with or without VD treatment.     

Genetics of parathyroid tumours

Primary hyperparathyroidism (PHPT), due to parathyroid tumours, may occur as part of a complex syndrome or as an isolated (nonsyndromic) disorder, and both forms can occur as familial (i.e. hereditary) or nonfamilial (i.e. sporadic) disease. Syndromic PHPT includes multiple endocrine neoplasia (MEN) types 1 to 4 (MEN1 to MEN4) and the hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome. Syndromic and hereditary PHPT are often associated with multiple parathyroid tumours, in contrast to sporadic PHPT, in which single parathyroid adenomas are more common. In addition, parathyroid carcinomas may occur in ~15% of patients with the HPT‐JT syndrome. MEN1 is caused by abnormalities of the MEN1 gene which encodes a tumour suppressor; MEN2 and MEN3 are due to mutations of the rearranged during transfection (RET) proto‐oncogene, which encodes a tyrosine kinase receptor; MEN4 is due to mutations of a cyclin‐dependent kinase inhibitor (CDNK1B); and HPT‐JT is due to mutations of cell division cycle 73 (CDC73), which encodes parafibromin. Nonsyndromic PHPT, which may be hereditary and referred to as familial isolated hyperparathyroidism, may also be due to MEN1, CDC73 or calcium‐sensing receptor (CASR) mutations. In addition, ~10% of patients presenting below the age of 45 years with nonsyndromic, sporadic PHPT may have MEN1, CDC73 or CASR mutations, and overall more than 10% of patients with PHPT will have a mutation in one of 11 genes. Genetic testing is available and of value in the clinical setting, as it helps in making the correct diagnosis and planning the management of these complex disorders associated with parathyroid tumours.