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Hair is an essential protective and health-maintaining covering for the body, especially the scalp. It is also important esthetically in modern society, where hair loss, whether caused by the severe scalp condition androgenic alopecia or other internal or external factors, has societal and psychological impacts. Preventing the apoptosis of human hair follicle cells, including hair follicle dermal papilla cells (HFDPCs) and human hair follicle keratinocytes (HHFKs), is crucial for hair production, alongside hair strengthening, which is essential in combatting hair loss. Given the structural importance of collagen peptides in the skin matrix and tissues surrounding hair follicles, we studied the function of AP collagen peptides (APCP) as a hair growth and quality improvement agent. APCP was found to stimulate the proliferation of hair follicle cells and counteract H2O2-induced apoptosis. It also significantly suppressed the expression of dickkopf-1 (DKK1) and bone morphogenetic protein 6 (BMP6), which induce hair cell apoptosis in the presence or absence of UVA/B irradiation. Moreover, APCP induced expression of the antioxidant enzymes, catalase and superoxide dismutase 1 (SOD1), while enhancing hair keratin expression in HHFKs. Mechanistically, APCP facilitated hair growth by elevating GAS6 expression and activating PKA and AKT/ERK signaling pathways. Notably, APCP increased levels of phosphor-β-catenin (Ser552/Ser675) as well as total β-catenin, as demonstrated by Western blotting and immunocytochemistry. Lastly, we showed that APCP increased expression of the hair cuticle type I keratins, keratin-32 and 42, in HHFKs. Overall, these findings propose APCP as a promising candidate for safeguarding hair follicle cells and mitigating hair loss by improving hair growth and quality.

We investigated the natural history of cholelithiasis in 59 samples of stones from the gallbladder or common bile duct in 15 patients, using as a tracer for the timing of stone formation the 14C released into the environment during nuclear weapons testing. The ages of the stones were correlated with the dates of onset of symptoms and with other clinical data. None of 11 symptomatic patients had symptoms or complications until at least two years (mean +/- SD, 8.0 +/- 5.1 years) after stone formation began. There was a lag time of 11.7 +/- 4.6 years between initial stone formation and cholecystectomy. The growth rates of stones from 11 symptomatic patients and 4 asymptomatic patients were similar (2.6 +/- 1.4 and 2.6 +/- 1.1 mm per year). Studies of two stones retrieved from the common bile duct showed that one had the same age as a cholecystic stone; the other, removed two years after cholecystectomy, apparently grew in the common bile duct. The long latency period between the formation of gallstones and the onset of symptoms indicates that interruption of the natural progression of gallstone disease is potentially possible with medical therapy.

A systematic review is conducted to identify effective interventions that improved adherence to antihypertensive drugs among patients with coronary heart diseases (CHDs). Primary studies designed to measure interventions to improve adherence on antihypertensive drugs in patients with CHD were included. Three online databases, COCHRANE, EMBASE and MEDLINE, were searched for primary studies published in English from 2005 to 2019. Studies were screened independently for eligibility. Cochrane risk-of-bias tool and the Newcastle-Ottawa Scale were used for quality assessment of randomised controlled trials (RCTs) and non-randomised studies, respectively. Of the 2000 entries identified, seven articles, including one cross-sectional study and six RCTs, met the inclusion criteria and were reviewed. One of the articles evaluated two interventions, so eight interventions were evaluated in total. Quality of the included studies was generally high, with the cross-sectional study rated as having good quality under Newcastle-Ottawa Scale, while four and two RCTs were rated as having low and some risk of bias under Cochrane risk-of-bias tool, respectively. Six of the intervention programmes were considered effective. An intervention was considered effective if it is associated with a significant (p≤0.05) and non-trivial (Cohen's d≥0.2) improvement in compliance-related outcomes such as in terms of the Morisky 8-item Medication Adherence Scale. Medication education, disease education, health education, constant reminders and medications dispensed using blister packs were identified to be effective in improving patients' compliance to medications. The importance of the continuity of interventions was also established. It is recommended that health service institutions should provide continuous education programmes, daily reminders and regular follow-ups for their patients who have CHD. It is recommended that further research ought to be carried out by using only one intervention in each trial with a standardised outcome measure, or using factorial designs, so that further cost-effectiveness evaluation of each intervention can be carried out independently, leading to the formulation of a comprehensive, optimised intervention programme for patients with CHD taking antihypertensives., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

We have investigated changes of western North Pacific land-falling tropical cyclone (TC) characteristics due to warmer climate conditions, using the pseudo-global-warming (PGW) technique. Historical simulations of three intense TCs making landfall in Pearl River Delta (PRD) were first conducted using the Weather Research and Forecasting (WRF) model. The same cases were then re-simulated by superimposing near- (2015-2039) and far- (2075-2099) future temperature and humidity changes onto the background climate; these changes were derived from the Coupled Model Intercomparison Project phase 5 (CMIP5) multi-model projections according to the Representative Concentration Pathway (RCP) 8.5 scenario. Peak intensities of TCs (maximum surface wind in their lifetimes) are expected to increase by ~ (3) 10% in the (near) far future. Further experiments indicate that surface warming alone acts to intensify TCs by enhancing sea surface heat flux, while warmer atmosphere acts in the opposite way by increasing the stability. In the far future, associated storm surges are also estimated to increase by about 8.5%, computed by the Sea, Lake, and Overland Surges from Hurricanes (SLOSH) model. Combined with sea level rise and estimated land vertical displacement, TC-induced storm tide affecting PRD will increase by ~1 m in the future 2075-2099 period.

Several human diseases are associated with aberrant epigenetic pathways mediated by histone deacetylases (HDACs), especially HDAC6, a class IIb HDACs, which has emerged as an attractive target for neurodegenerative and autoimmune disease therapeutics. In a previous study, we developed the novel HDAC6-selective inhibitor 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) and showed that it has anti-sepsis activity in vivo. In this study, we conducted structure-activity relationship (SAR) studies to optimize the activity and selectivity of HDAC6, synthesizing its derivatives with various aliphatic linker sizes and cap structures. We identified 6u ((E)-N-hydroxy-3-(2-(4-fluorostyryl)thiazol-4-yl)propanamide), which has nanomolar inhibition activity and a 126-fold selectivity for HDAC6 over HDAC1. Through the docking analyses of 6u against HDAC subtypes, we revealed the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Thus, we suggest a new rationale for the design of HDAC6-selective inhibitors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Preventing adolescent smoking is important as smoking is typically initiated by young people. This article reviews the prevalence, psychosocial correlates, and prevention of smoking in Hong Kong adolescents. The past 30-day smoking prevalence in adolescents decreased from 9.6% in 2003 to 2.5% in 2017. Tobacco advertisements, parental and best friends smoking, nonintact families, poor family relationships, lower socioeconomic status, being a new immigrant, poor knowledge of smoking-related harm, positive attitudes toward smoking, overestimation of peer smoking, and depressive symptoms were positively associated with smoking outcomes, whereas positive youth development, authoritative mother and permissive father, family functioning, school competence, and stronger tobacco industry denormalization beliefs were protective against smoking. Along with tobacco tax increase, ban on tobacco advertisements, smoke-free law and pictorial warnings, educational efforts through theater performances, social norms campaigns, and positive adolescent training programs have been conducted to prevent adolescent smoking. To achieve the ultimate goal of tobacco endgame, further tax increase, plain packaging, banning point-of-sale display of tobacco products, smoke-free area extension, and raising minimum age of purchase should be implemented. The government proposed law to ban e-cigarettes, and heated tobacco products should be passed soon to protect children and adolescents from using these products., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Information on respiratory viruses in subtropical region is limited.Incidence, mortality, and seasonality of influenza (Flu) A/B, respiratory syncytial virus (RSV), adenovirus (ADV), and parainfluenza viruses (PIV) 1/2/3 in hospitalized patients were assessed over a 15-year period (1998-2012) in Hong Kong.Male predominance and laterally transversed J-shaped distribution in age-specific incidence was observed. Incidence of Flu A, RSV, and PIV decreased sharply from infants to toddlers; whereas Flu B and ADV increased slowly. RSV conferred higher fatality than Flu, and was the second killer among hospitalized elderly. ADV and PIV were uncommon, but had the highest fatality. RSV, PIV 2/3 admissions increased over the 15 years, whereas ADV had decreased significantly. A "high season," mainly contributed by Flu, was observed in late-winter/early-spring (February-March). The "medium season" in spring/summer (April-August) was due to Flu and RSV. The "low season" in late autumn/winter (October-December) was due to PIV and ADV. Seasonality varied between viruses, but predictable distinctive pattern for each virus existed, and temperature was the most important associating meteorological variable.Respiratory viruses exhibit strong sex- and age-predilection, and with predictable seasonality allowing strategic preparedness planning. Hospital-based surveillance is crucial for real-time assessment on severity of new variants.

Rotavirus is a leading cause of severe infectious diarrhea in infants and young children aged <5 years. Rotavirus infections have minimal to strong seasonality depending on geographical locations. In this study, a comprehensive retrospective analysis was performed to evaluate the association between rotavirus admission and multiple key meteorological variables, including air temperature, relative humidity, atmospheric pressure, and solar radiation over a 15-year period from 1995 to 2009 in Hong Kong. Rotavirus infections were found to show a distinct cyclical pattern with an annual peak in cold season. The weekly number of cases showed the strongest correlation with average air temperature of the previous 7 days (rho=-0.69; P<0.0001), followed by atmospheric pressure (rho=+0.67; P<0.0001); whereas only weak correlation with relative humidity (rho=-0.252; P<0.0001) and solar radiation (rho=-0.312; P<0.0001) was observed. Curve fitting regression analysis suggested that the correlation was nonlinear in nature in which the effect was more profound towards lower air temperature and higher atmospheric pressure conditions. In binary logistic regression analysis, a final model that included air temperature (≤ 20°C) and atmospheric pressure (≥ 1,013 hPa) predicted correctly 85.3% and 82.6% of weeks with rotavirus activity above and below the baseline level, respectively. In multivariate Poisson model, air temperature and solar radiation were independent factors associated with the weekly number of rotavirus cases, adjusted for seasonal variation. In summary, the current study provides evidence suggesting that local seasonal activity of rotavirus correlated strongly with air temperature, followed by atmospheric pressure but only minimally with relative humidity in pre-vaccine era., (Copyright © 2013 Wiley Periodicals, Inc.)

The screening of a small focused library of rhodanine derivatives as inhibitors of Bcl-2 proteins led to the discovery of two structurally related compounds with different binding profiles against the Bcl-XL and the Mcl-1 proteins. Subsequent NMR studies with mutant proteins and in silico docking studies provide a possible rationale for the observed specificity.

The type IVb pilus of the enteropathogenic bacteria Salmonella typhi is a major adhesion factor during the entry of this pathogen into gastrointestinal epithelial cells. Its target of adhesion is a stretch of 10 residues from the first extracellular domain of cystic fibrosis transmembrane conductance regulator (CFTR). The crystal structure of the N-terminal 25 amino acid deleted S. typhi native PilS protein (DeltaPilS), which makes the pilus, was determined at 1.9 A resolution by the multiwavelength anomalous dispersion method. Also, the structure of the complex of DeltaPilS and a target CFTR peptide, determined at 1.8 A, confirms that residues 113-117 (NKEER) of CFTR are involved in binding with the pilin protein and gives us insight on the amino acids that are essential for binding. Furthermore, we have also explored the role of a conserved disulfide bridge in pilus formation. The subunit structure and assembly architecture are crucial for understanding pilus functions and designing suitable therapeutics against typhoid.

Influenza seasons appear consistently in the temperate regions, but are more variable in tropical/subtropical regions. The determinant for such variation remains poorly understood. This study documented the activity of influenza over a 10-year period in Hong Kong; examining its association with changes in temperature and relative humidity. The two types of influenza exhibited different correlations with meteorological variations. Influenza A showed two seasonal peaks occurring respectively in winter/spring and summer months in most years. Influenza B showed a clear winter/spring peak, but its activity during summer months was more variable. Cold and humid conditions were associated with a higher activity of both influenza A and B. In contrast, hot and humid conditions were associated with a higher activity of influenza A, but were associated with only a moderate, less consistent increase in the activity of influenza B. A trend of increase in the magnitude of summer peaks of influenza A, but not influenza B, was observed. A hypothetical 2 degrees C rise in temperature would decrease the proportion of favorable days for influenza A in December-April from 78% to 57%, but an increase from 58% to 71% in May-November; with a similar effect (from 83% to 62%) for influenza B during December-April, but a modest change (from 17% to 18%) during May-November. The presence of two seasonal peaks of influenza annually emphasizes the need to evaluate the duration of protective immunity offered by vaccination. Further study on the effects of climate change and global warming on the activity of influenza is warranted.

Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.

Objective: It is generally agreed that there is a seasonal variation in the prevalence of cutaneous manifestations of systemic lupus erythematosus (SLE). We investigated whether there is seasonal variation in the incidence of noncutaneous lupus flare in Hong Kong., Methods: We reviewed all noncutaneous lupus flare in 222 consecutive patients with SLE followed in our clinic from 1995 to 2005. Specific organ involvement of each flare was reviewed. The variation in the prevalence of lupus flare by calendar month and the relation with climatic factors were determined., Results: The total followup was 18,412 patient-months. In total, there were 313 episodes of noncutaneous flare recorded in 129 patients. There were more lupus flares in December and January [2.31 episodes, vs 1.58 episodes per 100 patient-months for other calendar months; relative risk (RR) 1.46, 95% CI 1.12-1.90, p = 0.004], and more flares of lupus nephritis in December and January (1.14 episodes, vs 0.60 episodes per 100 patient-months for other calendar months; RR 1.90, 95% CI 1.29-2.80, p = 0.001). There were more cases of membranous nephropathy in December and January (0.46 episode, vs 0.18 episode per 100 patient-months for other calendar months; RR 2.59, 95% CI 1.36-4.93, p = 0.0027), while the variation in prevalence of proliferative lupus nephritis was not statistically significant. There was also a significant U-shape correlation between the rate of lupus flare and the monthly average environmental temperature (r = 0.802, p = 0.0096), with higher flare rate at extremes of temperature., Conclusion: We found substantial seasonal variation in the incidence of noncutaneous flare in our SLE patients, with peak incidence in December and January. There was a U-shaped relation between environmental temperature and the prevalence of noncutaneous flare. Keeping a warm living environment and avoiding exposure to extremes of temperature may help to reduce flare for SLE patients in subtropical countries.

The structure determination of PilS, a type IV pilin, by X-ray crystallography is reported. The recombinant protein from Salmonella typhi was overexpressed, purified and crystallized. The crystals belong to space group P2(1)2(1)2, with unit-cell parameters a = 77.88, b = 114.53, c = 31.75 A. The selenomethionine derivative of the PilS protein was overexpressed, purified and crystallized in the same space group. Data sets have been collected to 2.1 A resolution from the selenomethionine-derivative crystal using synchrotron radiation for multiwavelength anomalous dispersion (MAD) phasing.

Hepatic outputs of biliary lipids can be measured by intestinal perfusion techniques, either during constant infusion of liquid formula into the duodenum or through-out a 24-hour period during which time three meals are given along with an overnight fast. The purpose of this study was to compare these two methods for estimating secretion of biliary lipids. In 21 subjects, mean hourly outputs measured during continuous feeding were highly comparable to those during intermittent feeding, showing that the constant infusion technique gave valid estimations of overall daily secretion rates of biliary lipids. On the other hand, the intermittent mode of feeding showed phasic changes of outputs and composition of biliary lipids in response to feeding and fasting apart from total outputs over 24 hours. However, it takes longer to complete and requires the use of a meal marker. By combining the intestinal perfusion technique with measurements of fecal excretion of neutral steroids and bile acids, this method may be used to estimate absorption of cholesterol and bile acids from the intestine. Thus, these measurements allow quantification of a number of parameters of the enterohepatic circulation.

In patients with cholesterol gallstones, there is a diminished bile acid pool and the bile becomes supersaturated with cholesterol. Medical treatment has been aimed at re-expanding the pool to improve cholesterol solubility in bile but as yet the factors controlling the size of the bile acid pool' are unknown. Therefore the role of the liver and intestine in controlling bile acid pool size in the rat was studied and the effect of experimental expansion of the pool on bile acid metabolism and bile lipid composition examined. Bile acid absorption was increased from ileum made hyperplastic by previous jejunectomy and hepatic bile acid synthesis was increased by phenobarbitone treatment. Both jejunal resection and phenobarbitone significantly increased the size of the bile acid pool from 32.2 +/- SEM 0.94 mumoles/100 g body weight to 42.2 +/- 1.71 and 44.4 +/- 2.03 respectively. However, the effects of these experimental manipulations on bile acid secretion rate, enterohepatic cycling frequency, and synthesis rates were quite different. Jejunectomy caused a 56% increase in bile acid secretion and more rapid cycling of the bile acid pool but the enhanced absorption did not depress bile acid synthesis. In contrast, phenobarbitone markedly increased synthesis from 14.5 +/- 1.42 mumoles.100 g BW(-1). 24 hr(-1) to 25.9 +/- 3.19 but there was no significant change in bile acid secretion and the choleresis seen after phenobarbitone was mainly due to an increase in the bile acid-independent fraction of bile flow. In these experimental studies in the rat, expansion of the bile acid pool did not significantly change bile lipid composition or cholesterol solubility in bile.

A new kindred with asymptomatic hypobetalipoproteinemia is reported. The proband, age 67, differs from previously described cases in several respects: (a) unusually low levels of low density lipoprotein (LDL) cholesterol (4-8 mg/dl); (b) normal triglyceride levels; (c) low levels of high density lipoprotein; (d) mild fat malabsorption; and (e) a defect in chylomicron clearance. On a high-carbohydrate diet his plasma triglyceride levels, instead of rising, actually fell. Turnover of triglycerides in very low density lipoproteins (VLDL) was low (2.8 mg/kg per h). Fractional catabolic rate of LDL protein was just above the normal range (0.655/d) but net turnover was <10% of normal (0.65 mg/kg per d). The half-life of his chylomicrons was 29 min, five times the normal value. Postheparin lipoprotein lipase activity was normal and apolipoprotein C-II, the activator protein for lipoprotein lipase, was present and functional. Apolipoprotein C-III(1), however, was not detected in the VLDL fraction, a finding previously reported in patients with abetalipoproteinemia. Fecal excretion of cholesterol was almost twice normal; total sterol balance was increased by congruent with40%. The unusual features in the proband that distinguish him from previously described cases and from his affected first-degree relatives suggested that, in addition to the basic gene defect affecting LDL metabolism, he might have a second abnormality affecting clearance of chylomicrons and VLDL. The ratio of apolipoprotein E(3) to E(2) in his VLDL fraction was 0.93, just below the lower limit of normal, suggesting heterozygosity for E(3) deficiency. Whether or not this contributes to his hypertriglyceridemia remains to be established.

Although, in suitable patients, oral chenodeoxycholic acid (CDCA) dissolves gallstones, the results of recent animal studies suggest that it might be hepatotoxic. Liver function was therefore studied in patients with gallstones before and during treatment with CDCA and liver biopsies were carried out both in patients with cholelithiasis given bile acid therapy and in those who had been given no medical treatment. In 25 patients treated with 0.5-1.5 g CDCA/day (7-20 mg kg body weight(-1) day(-1)) there was no significant change in serum bilirubin, albumin, globulin, transaminase, isocitric dehydrogenase, alkaline phosphatase, and gamma glutamyl transpeptidase levels before and at monthly intervals during six months' treatment. The kinetics of bromsulphthalein (BSP) clearance and its apparent transport maximum were not significantly changed during CDCA therapy. The mean fasting serum bile acid concentrations of 18.0 +/- SEM 1.2 mumoles/litre before and 20.0 +/- 3.5 mumoles/litre during treatment were both significantly greater than control values. Liver histology was not appreciably different in 11 patients treated with CDCA from that in eight patients with untreated cholelithiasis and in three patients who had received CDCA three to four months before biopsy. These results suggest that in doses of 0.5 to 1.5 g/day CDCA is not hepatotoxic in man.

Because the action of rifampin induces hepatic microsomal enzymes, a study was carried out in four patients to determine whether this drug alters the composition of biliary lipids. Several different measurements were made while patients were both on and off rifampin therapy for various infective processes. These measurements included multiple determinations of lipid composition of gallbladder bile, the relative proportions f individual bile acids, and kinetics of cholic acid and chenodeoxycholic acid. In all four patients, the saturation of gallbladder bile increased during rifampin treatment, and the bile consistently became supersaturated. The relative portions of chenodeoxycholic acid and cholic acid were essentially unchanged by treatment, but total synthesis of bile acids increased in three tested patients with rifampin therapy. These results indicate that rifampin increases saturation of bile with cholesterol, but this increase is not due to a reduction in bile acid production.

A method has been developed for measurement of fractional clearance rates of chylomicrons in man. The technique employs constant infusion of emulsified fat into the duodenum at a rate of 200 mg/kh/hr. After 5 hr of infusion, concentrations of triglycerides (TG) in the chylomicron fraction become constant for the subsequent 5 hr. Since the input of chylomicron-TG is known, fractional removal rates can be calculated from steady-state plasma levels. In 21 patients with normal TG levels, clearance rates for chylomicrons were extremely rapid (t1/2 for chylomicron-TG equals 4.5 +/- 2.9 (SD) min). In 30 patients with endogenous hypertriglyceridemia, clearance was generally prolonged (t1/2 equals 23 +/- 5.5 min). This delay in chylomicron clearance could have been due either to a defect in removal of all TG-rich lipoproteinarticles; a generalized defect in clearance capacity for plasma TG was apparently ruled out for most patients by the further observation that reduction of endogenous TG by caloric restriction caused chylomicron removal to return to normal. These studies also showed that endogenous-TG is removed much less efficiently than chylomicron-TG, and in some patients, this discrepancy is particularly marked.

We have evaluated the efficacy of plant sterol preparations from two different sources and in two different physical forms in lowering the plasma cholesterol of a total of 46 patients with type II hyperlipoproteinemia when given in addition to appropriate diet therapy. In addition, the mechanisms of the hypocholesterolemic effect were investigated in 7 patients by a sterol balance technique. The maximal mean cholesterol lowering in response to any preparation was 12 percent, although it was much greater in some individual patients. Sterol balance data showed that plant sterols inhibit cholesterol absorption with maximal negative cholesterol balance in adults at a dose of 3 g/day of a tall oil sterol suspension. Interestingly, maximal plasma cholesterol reduction in the adult outpatients on this preparation was seen at the same dose level. Since the tall oil sterol suspension is relatively palatable and is poorly absorbed, it has potential value as an adjunct to dietary therapy in patients with mild hypercholesterolemia for whom long-term drug therapy is deemed advisable.

One of the potential complications of bile acid therapy for gallstone disease is the promotion of intestinal absorption of cholesterol, thereby increasing the influx of cholesterol in body pools. To determine whether bile acid feeding is associated with an increased absorption of intestinal cholesterol, absorption measurements were made in 8 obese subjects given chenodeoxycholic acid (CCDA) or Bilron (750 mg/day). The bile acids were given in random order, separated by control periods, in patients undergoing weight reduction. Absorption of cholesterol (mass and percent) and of bile acids were determined by a technique of combined measurements of biliary lipid secretion and fecal steroid excretion. Our data showed that during treatment with either bile acid, a marked increase in pool size and hepatic secretion of bile acids occurred. However, despite an increased flux of bile acids through the intestinal tract, there was no significant increase in cholesterol absorption as compared to control periods. Absorption rates during administration of the two bile acids were approximately the same. Furthermore, plasma cholesterol concentrations were stable throughout both control and treatment periods. Bile acid absorption remained highly efficient (greater than 96%) during all periods, even with administration of exogenous bile acids.

The mechanisms for the hypolipidemic action of nicotinic acid were examined in 12 patients with hyperlipidemia. Most patients were studied in the hospital on a metabolic ward. The first month was a control period followed by 1 month on nicotinic acid. During treatment with nicotinic acid, the triglycerides (TG) decreased in total plasma by an average of 52% and in very low density lipoproteins (VLDL) by 36%. Transport rates of VLDL-TG were determined by multicompartmental analysis following injection of [3H]glycerol as a precursor. Nicotinic acid decreased transport (synthesis) of VLDL-TG by an average of 21%. Kinetic modeling of the VLDL-TG data suggested that the TG reduction was due to a decrease in TG content of VLDL and hence a reduction in lipoprotein size more than number. For the whole group, plasma cholesterol fell during nicotinic acid therapy by a mean of 22%. The drug produced no detectable changes in fecal excretions of cholesterol (neutral steroids) or bile acids. However, it induced a small but significant increment in hepatic secretion of biliary cholesterol that might have led to a net loss of cholesterol from the body even though this loss could not be detected by sterol balance. Despite this increase in outputs of biliary cholesterol, there was not a significant increase in molar % cholesterol or in % saturation of gallbladder bile. Therefore, it is doubtful that nicotinic acid enhances the risk for cholesterol gallstones.

The ultrasonic absorption of myoglobin has been measured by the resonance and pulse-echo techniques as a function of pH. The absorption at a given frequency can be separated into pH-dependent and pH-independent contributions. Like other proteins, two peaks at pH 3 and 11.5 are observed which can be accounted for a proton-transfer reactions of the side-groups. In addition, the absorption undergoes a large increase within a small range of 0.2 pH unit at pH around 4, when denaturation of myoglobin occurs, indicating that the absorption is sensitive to the overall protein conformation. To elucidate the origin of the pH-independent component, the absorptions of several other globular proteins at neutral pH are also measured. The absorptions of these proteins exhibit a linear correlation with their isothermal compressibilities, suggesting that the pH-independent component is related to volume fluctuations of protein molecules. The activation energy of 4 kcal/mol found for this relaxation is consistent with such an interpretation.

In this study a technique is described for estimating net absorption of total cholesterol (endogenous + exogenous) that enters the intestine. The method employs intubation of patients with a 3-lumen tube that contains a 10-cm mixing segment in the duodenum and a 100-cm absorption segment in the jejunum. A liquid formula diet containing varying amounts of exogenous cholesterol is infused continuously into the upper duodenum for a period of several hours; the formula diet stimulates constant contraction of the gallbladder and thus provides for continous secretion of biliary cholesterol sitosterol as a marker, the input of endogenous + exogenous cholesterol can be measured at the end of the 10-cm mixing segment. Net cholesterol absorption is estimated from the disappearance of cholesterol relative to beta-sitosterol over the next 100-cm of jejunum. When radioactive cholesterol was also used as a marker, radioactivity usually disappeared more rapidly than the mass of choleesterol over the absorption segment; this suggests that a significant amount of isotope exchange occurs in the upper intestine. Using beta-sitosterol as a marker, the extent of exchange can be determined. In six patients, cholesterol inputs ranged from 51 to 118 mg/hr, and net percentage absorption was 34-56%. When inputs of cholesterol were acutely increased by enhancing exogenous cholesterol, absolute absorption was uniformly increased, but percentage absorption either remained the same or was decreased somewhat. Changine inputs of beta-sitosterol had a striking effect on cholesterol absorption, and relatively small increments of beta-sitosterol almost always produced corresponding reductions in uptake of cholesterol. The intestinal perfusion method appears to provide certain advantages over previous techniques for estimating total cholesterol entering the upper intestine, including that derived from both endogenous and exogenous sources. Measurements can be made over short periods of time, and the method allows for determination of effects of acute changes in the intestinal milieu on cholesterol absorption. Finally, the technique defines the extent of isotope exchange between cholesterol in the intestinal mucosa and in the lumen.

Obese subjects are prone to supersaturated bile, which is maintained or increased during weight loss. In this report, two related studies were carried out on obese subjects to investigate effects of bile acid feeding on biliary lipid metabolism before and during weight reduction. In one study, chenodeoxycholic acid (CDCA), 750 mg/day, was given to 12 obese subjects during weight maintenance (1st mo) and during weight reduction (2nd mo). In the second study, effects of two bile acid preparations, CDCA and Bilron (containing mostly cholic acid and deoxycholic acid), randomly administered, were compared in another 12 obese subjects undergoing weight reduction. The results show that obese subjects had large pools of bile acids during weight maintenance which decreased on caloric restriction (1,000 kcal/day). CDCA increased pool size only modestly during weight maintenance, from 3,536 +/- 1,267 (SD) mg to 4,735 +/- 1,434 mg. Both CDCA and Bilron markedly reexpanded the contracted pool of bile acids in obese subjects on weight reduction. However, significantly reduced saturation of bile occurred only in those on CDCA and weight reductions, whereas supersaturation was unaltered when weight was maintained constant in these patients, or when Bilron was given. No significant side effects were noted during bile acid feeding for any of the subjects. Thus, CDCA given to obese subjects on weight reduction will reduce bile saturation and could protect against gallstones.

We treated 70 patients with gallstones with chenodeoxycholic acid over 3 1/2 years and analyzed the factors influencing the outcome of therapy. This treatment was unsuccessful in 11 patients with radiopaque gallstones and in seven with nonfunctioning gallbladders, but 64 per cent with radiolucent gallstones treated for six months or more showed partial or complete gallstone dissolution, and of those whose bile became unsaturated with cholesterol, 100 per cent had evidence of dissolution. In patients with partial or complete gallstone dissolution, the mean post-treatment biliary cholesterol saturation index--0.78 +/- 0.04 (S.E.M.)--was significantly less (P less than 0.001), and the dose of chenodeoxycholic acid (14.4 +/- 1.0 mg per kilogram of body weight per day) significantly more (P less than 0.025) than in those whose gallstones did not change (1.15 +/- 0.04 and 10.6 +/- 1.2 respectively). In patients with radiolucent gallstones, the dose of chenodeoxycholic acid should be based on body weight; 14 to 15 mg per kilogram of body weight per day effectively lowers the saturation index and dissolves gallstones.

Medical dissolution of gallstones is feasible and has worked in clinical practice. Cholelithiasis is both common and a cause of significant morbidity nationally. Thus, to readdress the question posed in the introduction, should there be a more aggressive detection of populations at risk to consider prophylactic or early treatment of gallstones, one has to consider the following. Is it cost effective to treat people with asymptomatic stones when one half of gallstones detected at autopsy have not caused trouble in life? Will the reduction of one health hazard create other hazards, such as colonic cancer? Is it improving the quality of the patient's life after successful treatment to have the person return every year for ultrasound or radiologic check-ups for recurrence of gallstones? We feel that despite the low morbidity and mortality of elective surgery, medical dissolution of gallstones is a viable alternative, but, as with most medical decisions, the pros and cons of any therapy for cholelithiasis will ultimately be a decision based on the physician, the patient, and the situation. On the basis of what has been discussed in this review, the approach to treatment should involve a rational understanding of all alternatives.

Studies were carried out to determine effects of combined chemotherapy in patients with hyperlipidemia. In one study, 14 patients were treated first with colestipol and then with the combination of colestipol and clofibrate. In a second study, six patients were given clofibrate followed by addition of phytosterols. The following measurements were made in most patients: (1) plasma lipid concentrations, (2) fecal excretions of neutral steroids and bile acids, and (3) lipid composition of gallbladder bile. In six patients of the first study, hepatic secretion rates of biliary lipids and pool sizes of bile acids were also estimated. In the first study, colestipol alone caused a marked increase in fecal bile acids that resulted in a sizable decrease in plasma cholesterol concentrations (average 21 percent). In several patients, however, triglycerides were increased somewhat by colestipol. Despite interruption of the enterohepatic circulation of bile acids, the bile acid pool was not reduced, since a compensatory increase took place in bile acid synthesis. Also, except in one patient who developed gallstones following institution of colestipol, saturation of gallbladder bile with cholesterol was not markedly increased by this drug alone. Addition of clofibrate frequently produced a further decrement in plasma cholesterol, and the mild hypertriglyceridemia induced by colestipol was reversed. However, colestipol plus clofibrate usually caused a striking increase in saturation of gallbladder bile. Previous studies have shown that clofibrate causes a flux of cholesterol from tissue pools by simultaneously decreasing cholesterol synthesis and increasing its excretion. To further increase cholesterol excretion, phytosterols, which block cholesterol absorption, were added to clofibrate in the second study. Although phytosterols did not cause a further reduction in plasma cholesterol in these particular patients, they nevertheless greatly enhanced cholesterol excretion.

In 14 patients with reflux esophagitis previously treated with antacids, the effects of addition of cimetidine on biliary lipids were studied. Each subject served as his own control, but no placebo medication was used. It was found that cimetidine (300 mg p.o. q.i.d.), over a 6-mo period of therapy, did not significantly alter lipid composition of fasting gallbladder bile, biliary lipid secretions, bile acid pool size, and its internal composition. In addition to detailed biliary studies, other observations were also made. Symptomatically, most of the patients responded favorably to cimetidine, and 9 of the 14 patients reported virtual elimination of bothersome symptoms while taking this medication. Concomitant with symptomatic improvement, daily antacid requirement was significantly reduced. Lower esophageal sphincter pressure was unaffected by cimetidine. No significant side effects were noted in this series of patients.

Measurements of transport of triglycerides (TG) in very low density lipoproteins (VLDL) were carried out in 59 patients by injection of radioactive glycerol, determinations of specific activities of VLDL-TG for 48 h thereafter, and treatment of the data by multicompartmental analysis. The patients were divided into three groups: normal weight (89-120% ideal weight), mildly obese (120-135% ideal weight), and markedly obese (135% ideal weight). They had varying levels of VLDL-TG ranging from normal to markedly elevated. In many subjects, there was a positive correlation between concentrations and transport of VLDL indicating that overproduction of VLDL-TG contributed to hypertriglyceridemia. In others, and particularly in several markedly obese subjects, transport rates were greatly increased without significant hypertriglyceridemia, suggesting that they had enhanced capacity to clear TG. In all groups, however, there were patients whose degree of hypertriglyceridemia seemed out of proportion to their transport rates. This finding and the fact that many patients have increased secretion of VLDL-TG without elevated plasma TG suggests that both overproduction of VLDL-TG and insufficient enhancement of clearance contributed to the development of hypertriglyceridemia.The data showed a poor correlation between transport rates determined by our multicompartment analysis and single-exponential analysis used previously by other investigators (r = 0.46); this comparison was not improved by segregating patients according to their degree of obesity. Although two conversion pathways (fast and slow synthetic paths) were required to fit the data, there was no correlation between transport rates and the ratio of the two pathways. Also, despite the known pathway of conversion of VLDL to low density lipoprotein, no correlation was found between VLDL-TG transport rates and estimated low density lipoprotein-cholesterol concentrations.

We have selected for this study a well-defined group of patients with moderately advanced but compensated alcoholic cirrhosis. They were well-nourished and had no ascites, varices, azotemia, or encephalopathy. Liver biopsy showed little or no necrosis and inflammation despite wide-spread fibrosis. Serum bilirubin, transaminase, alkaline phosphatase, albumin and globulins were essentially normal. Biochemical evidence for liver disease was restricted to modest elevation of BSP retention, gamma GTP, serum bile acid concentrations, and urinary bile acid excretion. Except for changes in the interrelationships among the three biliary lipids, they were generally spared the abnormalities of sterol metabolism described in other patients with more advanced, more active liver disease. Thus, striking abnormalities in the metabolism of cholesterol and bile acids probably require severe reductions in functioning hepatocellular mass, major portal-systemic shunting, high disease activity, or all three to become manifest.