Publications

As a mediator of the effects of leptin, the melanocortin-4 receptor (MC4R) is an essential component of the central regulation of long-term energy homeostasis. Heterozygous mutations in this receptor are the most frequent genetic cause of severe obesity in children. The very rare described carriers of homozygous MC4R mutations for whom clinical data were available had a residual receptor activity thus not allowing for the description of the full extent of the role of MC4R in humans. Here, we present the clinical and biological features of a patient with complete absence of MC4R activity and compare the clinical and endocrine characteristics of this patient with those previously observed in leptin receptor-deficient patients. Our data suggest that in humans, the MC4R mediates most of the anorectic effects of leptin in early childhood. In contrast, MC4R does not mediate the effect of leptin on linear growth and other endocrine axes. In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia as recently observed in children with heterozygous MC4R mutations.

UNLABELLED

We diagnosed Fanconi's syndrome (phosphate depletion and dysfunction of the renal tubules) in three HIV(+) patients. This was temporally related to their HIV treatment. Physicians caring for patients with HIV should recognize the association of this rare syndrome with antiretroviral medications and monitor their patients carefully.

INTRODUCTION

Fanconi's syndrome is caused by increased excretion of phosphate, glucose, amino acids, and other intermediary metabolites, and can result in osteomalacia.

MATERIALS AND METHODS

We diagnosed this syndrome in three HIV(+) patients.

RESULTS

The first was a 43-year-old woman referred for multiple painful stress fractures. She demonstrated hypophosphatemia, metabolic acidosis, phosphaturia, glucosuria, and generalized aminoaciduria. These abnormalities resolved with oral phosphate replacement and discontinuation of the antiretroviral medication tenofovir. The second patient was a 39-year-old man with hypophosphatemia and bone pain. His symptoms improved with discontinuation of adefovir and supplementation of phosphate, potassium, and calcitriol. The third patient was a 48-year-old man who presented with symptomatic tetany caused by hypocalcemia (total serum calcium of 6.5 mg/dl [8.5-10.5 mg/dl]). Nine months before presentation, he had been treated with cidofovir for retinitis caused by cytomegalovirus. With calcium, phosphate, potassium, and calcitriol therapy, his laboratory abnormalities improved substantially, although he continues to require daily electrolyte replacement.

CONCLUSIONS

Each patient demonstrated generalized renal tubular dysfunction temporally related to treatment with antiretroviral drugs. The mechanism responsible for these abnormalities is not known; however, physicians caring for patients with HIV disease should recognize the association of Fanconi's syndrome with antiretroviral medications and monitor susceptible patients to prevent potential skeletal and neuromuscular complications.

Increased cGMP-specific phosphodiesterase (PDE5) activity in renal inner medullary collecting duct (IMCD) cells contributes to resistance to atrial natriuretic peptide (ANP) and the excessive sodium retention seen in experimental nephrotic syndrome and liver cirrhosis. Normal pregnancy is also accompanied by sodium retention and plasma volume expansion, and pregnant rats are resistant to the natriuretic action of ANP. The authors investigated a possible role of increased renal PDE5 activity in the physiologic sodium retention of normal rat pregnancy. The natriuresis and increased urinary cGMP excretion (U(cGMP)V) evoked by acute volume expansion (a measure of renal responsiveness to endogeneous ANP) was blunted in 16-d pregnant versus virgin rats, despite equivalent increases in circulating ANP in pregnants and virgins. The ANP-dependent cGMP accumulation in isolated IMCD cells from pregnants was blunted versus virgins and restored by the PDE5-selective antagonist DMPPO (10(-7) mol/L). PDE5 activity in vitro and PDE5 protein abundance in IMCD were greater in pregnants. Four days postpartum, volume expansion natriuresis, U(cGMP)V, and PDE5 protein levels in IMCD cell homogenates had returned to virgin values. These results demonstrate that normal rat pregnancy leads to in vivo and in vitro renal resistance to ANP, in association with heightened activity of the cGMP-specific PDE5 in IMCD. This may contribute to the physiologic sodium retention of normal pregnancy.

BACKGROUND

Psychosocial working conditions are likely to contribute to work-related musculoskeletal disorders (WRMSDs), but a lack of standardized measurement tools reflects both the theoretical and methodological limitations of current research.

METHODS

An interdisciplinary team including biomedical, behavioral, and social science researchers used an iterative process to adapt existing instruments for an interviewer-administered questionnaire assessing psychosocial workplace exposure related to musculoskeletal disorders.

RESULTS

The resulting questionnaire included measures of psychosocial workplace factors based on two theoretical models (the demand-control-support and the effort-reward imbalance models), supplemented by the additional constructs of "emotional demands," and "experiences of discrimination." Other psychosocial and physical measures selected for questionnaire inclusion address physical workload, sociodemographic and anthropometric characteristics, social relations and life events, health behaviors, and physical and psychological health.

CONCLUSION

Using an interdisciplinary approach facilitated the development of a comprehensive questionnaire inclusive of key measures of psychosocial factors that may play a role in the complex mechanisms leading to WRMSDs.

Sweat collection patches are used for drug abuse monitoring. We investigated the effect of sweat patch location (back and shoulder) on cocaine levels after controlled intravenous cocaine exposure (210 mg/70 kg) in 12 subjects (Experiment 1). Gas chromatographic-mass spectrometric analyses show cocaine and metabolites levels in Pharmchek trade mark patches were eightfold higher on the back than those on the shoulders. To assess the mechanisms for possible loss of cocaine from patches during wear, 48 sweat patches with a small amount of cocaine-d(5) (100 ng as base/patch) were placed on the backs of eight cocaine-naive volunteers for up to 72 h (Experiment 2). Drug-free patches were applied over eight of the cocaine-d(5) (100 ng) containing patches to measure loss through the patch. Cocaine levels in spiked patches declined over time (p = 0.002), with levels at 48 h postapplication 30% less than control, consistent with possible drug reabsorption. Cocaine was detectable (> 2 ng/patch, LOQ) in four of eight initially cocaine-free patches placed on top of the cocaine-containing patches, indicating transfer through the patch outer membrane. Conversion to benzoylecgonine was detectable but at low levels (< 2%). Reabsorption (back transfer), degradation or hydrolysis, and loss of cocaine to the environment may account for substantial loss of cocaine from skin sweat collection patches during patch wear.

Infections caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are emerging as a major public health problem. CA-MRSA has been associated previously with skin and soft-tissue infection (SSTI) and with carriage of staphylococcal cassette chromosome mec (SCCmec) type IV and the Panton-Valentine leucocidin (PVL) virulence factor. To assess the clonal distribution of PVL-carrying strains and the association with SSTI in the San Francisco Bay area, we surveyed six collections of S. aureus isolates-671 isolates in all-collected between 1997 and 2002 originating from inpatient and outpatient clinical specimens and from a community-based sampling. Isolates were genotyped by pulsed-field gel electrophoresis, multilocus restriction fragment typing, and multilocus sequence typing and assayed for the PVL virulence factor. The S. aureus populations showed a high proportion of PVL-carrying strains, with frequencies ranging up to 70% in MRSA isolated from jail inmate patients and 69% in MRSA from patients receiving surgical treatment at an outpatient clinic specializing in treating SSTIs. PVL-carrying isolates were identified in nine clonal groups, but 88.5% of the PVL-carrying MRSA isolates belonged to only two clonal groups. These two clonal groups carried the SCCmec type IV resistance determinant and were more likely than other clonal groups to be recovered from SSTI sites than from other sites (P < 0.0001). There is evidence of clonal replacement over the period from 1999 to 2002, with one of these two clonal groups being supplanted by the other.