Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice.

Alzheimer's disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/- mice were implanted with 17ß-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice- -thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquasition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/- mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid ß40 isoform in whole brain extracts. Finally, serum FSH levels < 8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

An Atlas of Brain-Bone Sympathetic Neural Circuits.

There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow--these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.

Evaluation of Montreal Cognitive Assessment (MoCA) Administered via Videoconference.

OBJECTIVES: Telemedicine provides much potential for promoting health care. The Montreal Cognitive Assessment (MoCA) is a screening tool for identifying mild cognitive impairment. This study aims to evaluate the agreement between MoCA assessed face-to-face vs via videoconference using a mobile phone. DESIGN: A randomized crossover study. SETTING AND PARTICIPANTS: A randomly selected sample of patients admitted to the geriatric rehabilitation department in a large tertiary medical center in 2021-2022. METHODS: The MoCA was conducted twice for each patient, with a 10- to 20-day interval between assessments. To avoid a learning effect, alternate MoCA versions were used for each patient. Intraclass correlation coefficient (ICC), kappa, weighted kappa, and the Bland-Altman plot were used to evaluate the agreement between administration methods. To identify variables associated with low agreement, data on participant characteristics, order of administration methods, and test versions were collected, and univariate and multivariable analyses were performed. RESULTS: Forty-four patients were included in the study. The median age was 83 years [interquartile range (IQR 76-87)] and 75% were females. Median overall MoCA score was 24 points (IQR 21-26) when administered face-to-face, and 23.5 points (IQR 21-26) via videoconference. Excellent agreement (ICC = 0.89) was observed in the total MoCA score. Moderate-substantial agreement was observed in subsection scores (kappa 0.436-0.686), except for the language subsection where fair agreement was observed (kappa 0.331). Anxiety was assessed by Hospital Anxiety and Depression Scale and associated with lower agreement (ICC = 0.76 in patients with anxiety vs ICC = 0.92 in patients without anxiety). None of the other studied variables were associated with a difference between administration methods. CONCLUSIONS AND IMPLICATIONS: Conducting a MoCA via videoconference using a mobile phone is another method of providing medical care to people without significant visual or hearing impairment that restricts their use of a mobile phone, during routine times and in emergencies where social distancing is needed.

Absent LH signaling rescues the anxiety phenotype in aging female mice.

Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as fertility hormones, in age-related cognitive decline. Furthermore, rising levels of LH in post-menopausal women have been implicated in the high prevalence of mood disorders. This study was designed to examine the effect of deficient LH signaling on both cognitive and emotional behavior in 12-month-old Lhcgr-/- mice. For this, we established and validated a battery of five tests, including Dark-Light Box (DLB), Y-Maze Spontaneous Alternation, Novel Object Recognition (NOR), and contextual and cued Fear Conditioning (FCT) tests. We found that 12-month-old female wild type mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in 12-month-old female Lhcgr-/- mice, indicating full phenotypic rescue. Furthermore, there was no effect of LHCGR depletion on recognition memory or working spatial memory on NOR and Y-maze testing, respectively, in 12-month-old mice, notwithstanding the absence of a basal phenotype in wild type littermates. The latter data do not exclude an effect of LH on cognition documented in previous studies. Finally, 12-month-old male mice and 3-month-old male and female mice did not consistently display deficits on any test. The data collectively document, for the first time, that loss of LH signaling reverses age-related emotional disturbances, a prelude to future targeted therapies that block LH action.

Development and biophysical characterization of a humanized FSH-blocking monoclonal antibody therapeutic formulated at an ultra-high concentration.

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the development of a unique formulation for our first-in-class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer's disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation's long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, confirmed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) Spectroscopy. Three rapid freeze-thaw cycles at -80 °C/25 °C or -80 °C/37 °C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80 °C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

Development and Biophysical Characterization of a Humanized FSH-Blocking Monoclonal Antibody Therapeutic Formulated at an Ultra-High Concentration.

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the creation of a unique formulation for our first-in- class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer's disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation's long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, conformed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) spectroscopy. Three rapid freeze-thaw cycles at -80°C/25°C or -80°C/37°C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (T m ) for formulated MS-Hu6 increased by >4.80°C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

Sex differences in heart failure patients assessed by combined echocardiographic and cardiopulmonary exercise testing.

Background: We aimed to test the differences in peak VO2 between males and females in patients diagnosed with heart failure (HF), using combined stress echocardiography (SE) and cardiopulmonary exercise testing (CPET). Methods: Patients who underwent CPET and SE for evaluation of dyspnea or exertional intolerance at our institution, between January 2013 and December 2017, were included and retrospectively assessed. Patients were divided into three groups: HF with preserved ejection fraction (HFpEF), HF with mildly reduced or reduced ejection fraction (HFmrEF/HFrEF), and patients without HF (control). These groups were further stratified by sex. Results: One hundred seventy-eight patients underwent CPET-SE testing, of which 40% were females. Females diagnosed with HFpEF showed attenuated increases in end diastolic volume index (P = 0.040 for sex × time interaction), significantly elevated E/e' (P < 0.001), significantly decreased left ventricle (LV) end diastolic volume:E/e ratio (P = 0.040 for sex × time interaction), and lesser increases in A-VO2 difference (P = 0.003 for sex × time interaction), comparing to males with HFpEF. Females diagnosed with HFmrEF/HFrEF showed diminished increases in end diastolic volume index (P = 0.050 for sex × time interaction), mostly after anaerobic threshold was met, comparing to males with HFmrEF/HFrEF. This resulted in reduced increases in peak stroke volume index (P = 0.010 for sex × time interaction) and cardiac output (P = 0.050 for sex × time interaction). Conclusions: Combined CPET-SE testing allows for individualized non-invasive evaluation of exercise physiology stratified by sex. Female patients with HF have lower exercise capacity compared to men with HF. For females diagnosed with HFpEF, this was due to poorer LV compliance and attenuated peripheral oxygen extraction, while for females diagnosed with HFmrEF/HFrEF, this was due to attenuated increase in peak stroke volume and cardiac output. As past studies have shown differences in clinical outcomes between females and males, this study provides an essential understanding of the differences in exercise physiology in HF patients, which may improve patient selection for targeted therapeutics.

Optimizing a therapeutic humanized follicle-stimulating hormone-blocking antibody formulation by protein thermal shift assay.

Biopharmaceutical products are formulated using several Food and Drug Administration (FDA) approved excipients within the inactive ingredient limit to maintain their storage stability and shelf life. Here, we have screened and optimized different sets of excipient combinations to yield a thermally stable formulation for the humanized follicle-stimulating hormone (FSH)-blocking antibody, MS-Hu6. We used a protein thermal shift assay in which rising temperatures resulted in the maximal unfolding of the protein at the melting temperature (Tm ). To determine the buffer and pH for a stable solution, four different buffers with a pH range from 3 to 8 were screened. This resulted in maximal Tm s at pH 5.62 for Fab in phosphate buffer and at pH 6.85 for Fc in histidine buffer. Upon testing a range of salt concentrations, MS-Hu6 was found to be more stable at lower concentrations, likely due to reduced hydrophobic effects. Molecular dynamics simulations revealed a higher root-mean-square deviation with 1 mM than with 100 mM salt, indicating enhanced stability, as noted experimentally. Among the stabilizers tested, Tween 20 was found to yield the highest Tm and reversed the salt effect. Among several polyols/sugars, trehalose and sucrose were found to produce higher thermal stabilities. Finally, binding of recombinant human FSH to MS-Hu6 in a final formulation (20 mM phosphate buffer, 1 mM NaCl, 0.001% w/v Tween 20, and 260 mM trehalose) resulted in a thermal shift (increase in Tm ) for the Fab, but expectedly not in the Fc domain. Given that we used a low dose of MS-Hu6 (1 µM), the next challenge would be to determine whether 100-fold higher, industry-standard concentrations are equally stable.

Bone circuitry and interorgan skeletal crosstalk.

The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.

Octa-nonagenarians can perform video capsule endoscopy safely and with a higher diagnostic yield than 65-79-year-old patients.

BACKGROUND: Video capsule endoscopy (VCE) is an effective, noninvasive modality for small bowel (SB) investigation. Its usage in the older adults is rising. However, data in octa-nonagenarians regarding diagnostic yield and motility are lacking. Our aim was to evaluate and compare safety and efficacy of VCE between age subgroups of older adult patients. METHODS: This was a retrospective study of prospectively documented data. All consecutive VCEs of patients ≥65 years (01/2010-12/2017) were included. Patients unable to swallow the capsule or videos with significant recording technical malfunction were excluded. The cohort was divided into the younger group aged 65-79 years old and octa-nonagenarians aged ≥80 years old. Indications for referral, diagnostic yield and transit times were compared between groups. RESULTS: A total of 535 VCEs were performed in 499 older adult patients (51.2% males); 82.8% were 65-79 years old and 17.2% were ≥80 years old. The ≥80-year-old group had higher rates of clinically significant findings (52.7% vs. 40.0%, p = 0.025), active bleeding (12.5% vs. 6.5%, p = 0.053) and angioectasia (36.0% vs. 23.4%, p = 0.014). Crohn's disease was newly diagnosed in approximately 8% of the entire cohort and 12% of the ≥80 years old. Anemia was the most common indication in both groups, followed by overt bleeding in the ≥80-year-old group (25% vs. 9.9% in 65-79-year-old group, p < 0.001) and Crohn's disease in the 65-79 years old (17.2% vs. 5.4% in ≥80 years old, p = 0.004). Groups were comparable in transit time and cecal documentation rates. CONCLUSIONS: In octa-nonagenarians, VCE is as safe as in younger older-adults with a higher diagnostic yield of significant and treatable conditions.

[NOT ONLY FOR CANCER PATIENTS - PALLIATIVE CARE FOR NON-ONCOLOGIC PATIENTS AT THE END OF LIFE IN A GERIATRIC - INTERNAL MEDICINE DEPARTMENT].

AIMS: This article presents our ongoing experience in the care of palliative patients suffering from non-oncologic diseases. BACKGROUND: Palliative care is an approach intended to improve quality of life in patients facing life-threatening illness. This approach entails early identification, thorough assessment and treatment of pain and suffering as well as establishing a goals-directed care plan in order to improve these patients' quality of life. While in oncology patients there is a steady increase in the awareness of the need for palliative care, in non-oncology patients there is a marked deficit regarding identification of patients needing palliative care, determination of goals of care and delivery of palliative care throughout the disease and at the end of life. Furthermore, there is a lack of appropriate platforms to deliver such care. In Israel, the majority of deaths occur in-hospital. Therefore, it makes sense to implement good palliative care platforms in hospitals, in order to meet the need for palliative care. In January 2018, we opened an inpatient palliative care unit within the Geriatric-Internal Medicine Department in the Tel Aviv Sourasky Medical Center. METHODS: This is a retrospective study of all the patients who died in the Geriatric Internal Medicine Department, during the period 1.1.2018-31.7.2020. RESULTS: A total of 2,335 patients were admitted to the ward during the period 1.1.2018-31.7.2020. Within this group, 371 (16%) died during hospitalization, 257 died from oncologic diseases, 8 died unexpectedly and 106 died from non-oncologic diseases. Patients who suffered from non-oncologic diseases were older, with a shorter length of stay (9.6 vs. 10.5 days) and were more likely to be bed-ridden. The most common cause of death was infection (48%), pneumonia being the most prevalent. Most end-of-life decisions were made during hospitalization, with the guidance of the next of kin. CONCLUSIONS: Patients suffering from non-oncologic diseases represent a considerable number of palliative care patients. However, there is a marked deficit in the ability to recognize their palliative needs, prognostication and therefore, identifying the right platform to care for them. We have described such a platform in the Geriatric Internal ward.

[TAILORED APPROACH TO THE GERIATRIC PATIENT WITH CANCER].

INTRODUCTION: Cancer became one of the most common clinical problems in the care of older adults. Cancer is the leading cause of death in Israel. Currently about 50% of cancer diagnoses occur in patients over 65 years of age, but this number is expected to increase to 70% by 2030. This is largely due to the shifting demographics, increasing life expectancy and improvements in the level of mortality from cardiovascular disease. The aging cancer population has an impact across the treatment spectrum from screening decisions, multimodality treatment options, survivorship and quality of life. This paper will review the approach to the principles of geriatric oncology within different treatment modalities.

Emergency department impaired adherence to personal protective equipment donning and doffing protocols during the COVID-19 pandemic.

OBJECTIVES: Coronavirus Disease 2019 (COVID-19) is a highly infectious viral pandemic that has claimed the lives of millions. Personal protective equipment (PPE) may reduce the risk of transmission for health care workers (HCWs), especially in the emergency setting. This study aimed to compare the adherence to PPE donning and doffing protocols in the Emergency Department (ED) vs designated COVID-19 wards and score adherence according to the steps in our protocol. DESIGN: Prior to managing COVID-19 patients, mandatory PPE training was undertaken for all HCWs. HCWs were observed donning or doffing COVID-19 restricted areas. SETTING: Donning and doffing was observed in COVID-19 designated Emergency department and compared to COVID-19 positive wards. PARTICIPANTS: All HCWs working in the aforementioned wards during the time of observation. RESULTS: We observed 107 donning and doffing procedures (30 were observed in the ED). 50% HCWs observed donned PPE correctly and 37% doffed correctly. The ED had a significantly lower mean donning score (ED: 78%, Internal: 95% ICU: 96%, p < 0.001); and a significantly lower mean doffing score (ED: 72%, Internal: 85% ICU: 91%, p = 0.02). CONCLUSIONS: As hypothesized, HCWs assigned to the designated ED wing made more protocol deviations compared with HCWs positive COVID-19 wards. Time management, acuity, lack of personnel, stress and known COVID-19 status may explain the lesser adherence to donning and doffing protocols. Further studies to assess the correlation between protocol deviations in use of PPE and morbidity as well as improvement implementations are required. Resources should be invested to ensure PPE is properly used.

Linking type 2 diabetes mellitus, cardiac hypertrophy and depression in a diurnal animal model.

It was recently suggested that the Metabolic Syndrome should be renamed to "Circadian Syndrome". In this context, we explored the effects of living under standard laboratory conditions, where light is the only cycling variable (relevant to human modern life), in a diurnal mammal, on the relationships between affective-like pathology, type 2 diabetes mellitus (T2DM), and cardiac hypertrophy. After 20 weeks, some of the animals spontaneously developed T2DM, depressive and anxiety-like behavior and cardiac hypertrophy. There were significant correlations between levels of anxiety-like behavior and glucose tolerance, and between heart/total body weight ratio and glucose tolerance. Our data suggest a relationship between the development of T2DM, emotional and cardiac pathology as seen in diurnal humans. Furthermore, our data show a possible relationship between reduced daily cycling cues in the laboratory and what has been regularly termed "Metabolic Syndrome" and recently proposed by us to be renamed to "Circadian Syndrome".

The effect of medical students' gender, ethnicity and attitude towards poetry-reading on the evaluation of a required, clinically-integrated poetry-based educational intervention.

BACKGROUND: Art-based interventions are widely used in medical education. However, data on the potential effects of art-based interventions on medical students have been limited to small qualitative studies on students' evaluation of elective programs, and thus their findings may be difficult to generalize. The goal of this study is to examine, in an unselected students' population, the effect of students' gender, ethnicity and attitude towards poetry on their evaluation of a clinically-integrated poetry-based educational intervention. METHODS: A required Clinically- Oriented Poetry-reading Experience (COPE) is integrated into the 4th year internal medicine clerkship. We constructed a questionnaire regarding the program's effects on students. Students completed the questionnaire at the end of the clerkship. We performed a Confirmatory Factor Analysis, and examined the relationship between students' evaluation of the program and students' ethnicity, gender, attitude towards poetry-reading, and the timing of the program (early/late) during the fourth year. RESULTS: 144 students participated in the program, of which 112 completed the questionnaires. We identified two effect factors: "student-patient" and "self and colleagues". The average score for "student-patient" factor was significantly higher as compared to the "self and colleagues" factor.Evaluation the "student- patient" effect factor was higher among Arab and Druze as compared to Jewish students. Students' attitude towards poetry-reading did not correlate with the "student-patient" effect, but correlated with the "self and colleagues" effect. The evaluation of the "self and colleagues" effect was higher among students who participated in the program during their second as compared with the first clerkship. Students' gender was not associated with any of the effects identified. Students favored obligatory participation in COPE as compared with elective course format. CONCLUSIONS: According to students' evaluation, a format of integrated, obligatory poetry-based intervention may be suitable for enhancing "student-patient" aims in heterogeneous student populations. The higher evaluation of the "patient-student" effect among Arab and Druze as compared to Jewish students may be related to cultural differences in the perception of this component of medical professionalism. Further research can provide insight into the effect of cultural and ethnic differences on actual empathy of medical students in patient encounters.

Trans-arterial chemo-embolization is safe and effective for elderly advanced hepatocellular carcinoma patients: results from an international database.

OBJECTIVE: Hepatocellular carcinoma (HCC) incidence among elderly patients is increasing. Trans-arterial chemo-embolization (TACE) prolongs survival in selected HCC patients. The safety and efficacy of TACE in elderly patients has not been extensively studied. The objective of this study was to assess the safety and efficacy of TACE in elderly patients (older than 75) with HCC. DESIGN: Combined HCC registries (Spain, Italy, China and Israel) and cohort design analysis of patients who underwent TACE for HCC. RESULTS: Five hundred and forty-eight patients diagnosed and treated between 1988 and 2010 were included in the analysis (China 197, Italy 155, Israel 102 and Spain 94,). There were 120 patients (22%) older than 75 years and 47 patients (8.6%) older than 80. Median (95% CI) survival estimates were 23 (17-28), 21 (17-26) and 19 (15-23) months (P=0.14) among patients aged younger than 65, 65-75 and older than 75 respectively. An age above 75 years at diagnosis was not associated with worse prognosis, hazard ratio of 1.05 (95% CI 0.75-1.5), controlling for disease stage, sex, diagnosis year, HBV status and stratifying per database. No differences in complication rates were found between the age groups. CONCLUSIONS: TACE is safe for patients older than 75 years. Results were similar over different eras and geographical locations. Though selection bias is inherent, the results suggest overall adequate selection of patients, given the similar outcomes among the different age groups.

Activity rhythms and masking response in the diurnal fat sand rat under laboratory conditions.

Daily rhythms are heavily influenced by light in two major ways. One is through photic entrainment of a circadian clock, and the other is through a more direct process, referred to as masking. Whereas entraining effects of photic stimuli are quite similar in nocturnal and diurnal species, masking is very different. Laboratory conditions differ greatly from what is experienced by individuals in their natural habitat, and several studies have shown that activity patterns can greatly differ between laboratory environment and natural condition. This is especially prevalent in diurnal rodents. We studied the daily rhythms and masking response in the fat sand rat (Psammomys obesus), a diurnal desert rodent, and activity rhythms of Tristram's jird (Meriones tristrami), a nocturnal member of the same subfamily (Gerbillinae). We found that most sand rats kept on a 12 h:12 h light-dark (LD) cycles at two light intensities (500 and 1000 lux) have a nocturnal phase preferences of general activity and higher body temperature during the dark phase. In most individuals, activity was not as stable that of the nocturnal Tritram's jirds, which showed a clear and stable nocturnal activity pattern under the same conditions. Sand rats responded to a 6-h phase advance and 6-h phase delay as expected, and, under constant conditions, all tested animals free ran. In contrast with the nocturnal phase preference, fat sand rats did not show a masking response to light pulses during the dark phase or to a dark pulse during the light phase. They did, however, have a significant preference to the light phase under a 3.5 h:3.5 h LD schedule. Currently, we could not identify the underlying mechanisms responsible for the temporal niche switch in this species. However, our results provide us with a valuable tool for further studies of the circadian system of diurnal species, and will hopefully lead us to understanding diurnality, its mechanisms, causes, and consequences.

Trans-arterial chemo-embolization is safe and effective for very elderly patients with hepatocellular carcinoma.

AIM: To assess the safety and efficacy of trans-arterial chemo-embolization (TACE) in very elderly patients. METHODS: A prospective cohort study, from 2001 to 2010, compared clinical outcomes following TACE between patients ≥ 75 years old and younger patients (aged between 65 and 75 years and younger than 65 years) with hepatocellular carcinoma (HCC), diagnosed according to the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases criteria. The decision that patients were not candidates for curative therapy was made by a multidisciplinary HCC team. Data collected included demographics, co-morbidities, liver disease etiology, liver disease severity and the number of procedures. The primary outcome was mortality; secondary outcomes included post-embolization syndrome (nausea, fever, abdominal right upper quadrant pain, increase in liver enzymes with no evidence of sepsis and with a clinical course limited to 3-4 d post procedure) and 30-d complications. Additionally, changes in liver enzyme measurements were assessed [alanine and aspartate aminotransferase (ALT and AST), gamma-glutamyl transpeptidase and alkaline phosphatase] in the week following TACE. Analysis employed both univariate and multivariate methods (Cox regression models). RESULTS: Of 102 patients who underwent TACE as sole treatment, 10 patients (9.8%) were > 80 years old at diagnosis; 13 (12.7%) were between 75 and 80 years, 45 (44.1%) were between 65 and 75 years and 34 (33.3%) were younger than 65 years. Survival analysis demonstrated similar survival patterns between the elderly patients and younger patients. Age was also not associated with the adverse event rate. Survival rates at 1, 2 and 3 years from diagnosis were 74%, 37% and 31% among patients < 65 years; 83%, 66% and 48% among patients aged 65 to 75 years; and 86%, 41% and 23% among patients ≥ 75 years. There were no differences between the age groups in the pre-procedural care, including preventive treatment for contrast nephropathy and prophylactic antibiotics. Multivariate survival analysis, controlling for disease stage at diagnosis with the Barcelona Clinic Liver Cancer score, number of TACE procedures, sex and alpha-fetoprotein level at the time of diagnosis, found no significant difference in the mortality hazard for elderly vs younger patients, and there were no differences in post-procedural complications. Serum creatinine levels did not change after 55% of the procedures, in all age groups. In 42% of all procedures, serum creatinine levels increased by no more than 25% above the baseline levels prior to TACE. Overall, there were 69 post-embolization events (23%). Hepatocellular enzymes often increased following TACE, with no association with prognosis. In 40% of the procedures, ALT and AST levels rose by at least 100%. The increases in hepatocellular enzymes occurred similarly in all age groups. CONCLUSION: TACE is safe and effective in very elderly patients with HCC, and is not associated with decreased survival or increased complication rates.

Conservative treatment for acute cholecystitis: clinical and radiographic predictors of failure.

BACKGROUND: Current treatment options for acute calculous cholecystitis include either early cholecystectomy, or conservative treatment consisting of intravenous antibiotics and an interval cholecystectomy several weeks later. Percutaneous drainage is reserved for patients in whom conservative therapy failed or as a salvage procedure for high risk patients. OBJECTIVE: To identify clinical and radiographic factors leading to failure of conservative treatment. METHODS: We prospectively collected data on consecutive patients admitted with the diagnosis of acute cholecystitis. Parameters were compared between patients who were successfully treated conservatively and those who required percutaneous cholecystostomy. Logistic regression analysis was performed to identify predictors for failure of conservative treatment. RESULTS: The study population comprised 103 patients with a median age of 60 who were treated for acute cholecystitis. Twenty-seven patients (26.2%) required PC. On univariate analysis, age above 70 years, diabetes, elevated white blood cell count, tachycardia (> 100 beats/min) at admission, and a distended gallbladder (> 5 cm transverse diameter) were found to be significantly more common in the PC group (P < 0.001). WBC was higher in the PC group throughout the initial 48 hours. On multivariate analysis, age above 70 (odds ratio 3.6), diabetes (OR 9.4), tachycardia at admission (OR 5.6), and a distended gallbladder (OR 8.5) were predictors for cholecystostomy (P < 0.001). Age above 70 (OR 5.2) and WBC $15,000 (OR 13.7) were predictors for failure of conservative treatment after 24 and 48 hours (P < 0.001). CONCLUSIONS: Age above 70, diabetes, and a distended gallbladder are predictors for failure of conservative treatment and such patients should be considered for early cholecystostomy. Persistently elevated WBC (> 15,000) suggests refractory disease and should play a central role in the clinical follow-up and decision-making process for elderly patients with acute cholecystitis.