The G209R mutant mouse as a model for human PCSK1 polyendocrinopathy.

PCSK1 encodes an enzyme required for prohormone maturation into bioactive peptides. A striking number of SNPs and rare mutations in PCSK1 are associated with a range of clinical phenotypes. Infants bearing two copies of a catalytically inactivating mutation, such as G209R, exhibit life-threatening chronic diarrhea and subsequently develop systemic endocrinopathies. Using CRISPR/Cas9 technology, we have engineered a mouse model bearing a G209R missense mutation in exon 6 of the murine Pcsk1 locus. Most pups homozygous for the G209R mutation succumbed by day 2, and surviving pups were severely dwarfed. In homozygous (but not heterozygous) pups, blood glucose levels were significantly lower, accompanied by elevated plasma insulin-like immunoreactivity and accumulation of large quantities of unprocessed proinsulin in the pancreas. Peptide hormone processing was also aberrant in G209R mouse pituitary, with mature ACTH levels markedly reduced in homozygotes, accompanied by a significant accumulation of POMC. We also observed a significant reduction in PC1/3 protein in the brains of G209R homozygous mice by Western blotting, while PC2 levels remained unaffected. Most likely due to the continued presence of PC2, pituitary and brain levels of α-MSH were not impaired. Analysis of intestinal cell types indicated a modest reduction of enteroendocrine cells in G209R homozygotes. We suggest that the G209R Pcsk1 mouse model recapitulates many of the dramatic neonatal deficiencies of human patients with this homozygous mutation.

Herpes Zoster Ophthalmicus.

Herpes zoster is a commonly encountered disorder. It is estimated that there are approximately 1 million new cases of herpes zoster in the United States annually, with an incidence of 3.2 per 1000 person-years. Patients with HIV have the greatest risk of developing herpes zoster ophthalmicus compared with the general population. Other risk factors include advancing age, use of immunosuppressive medications, and primary infection in infancy or in utero. Vaccination against the virus is a primary prevention modality. Primary treatments include antivirals, analgesics, and anticonvulsants. Management may require surgical intervention and comanagement with pain specialists, psychiatrists, and infectious disease specialists.

Awareness of Human Papillomavirus Vaccine Among Adolescent African American Males Who Have Sex with Males: a Pilot Study.

African American adolescent males who have sex with males (MSMs) have a high prevalence of sexually transmitted diseases (STDs) that has been directly linked to lack of access to primary care providers and reluctance to disclose their sexuality. The human papillomavirus (HPV) is the most common STD with more than 40 different serotypes and can lead to anal/genital warts as well as oral and genital cancers. The HPV vaccine if taken prior to an adolescent becoming sexually active serves a prophylactic function. The HPV vaccine is approved by the Food and Drug Administration (FDA) for girls and boys; however, HPV vaccination rates among adolescents within different minority and underserved communities have been disappointing even though these groups are disproportionately infected with the HPV virus and certain male-specific cancers. Little is known about the uptake of the vaccine among African American MSMs and thus the aim of this study. This qualitative study is based on the health belief model and assessed participants' level of awareness of HPV, the HPV vaccine, and HPV-related illnesses among 24 African American male adolescents between 16 and 18 years old who self identify as MSMs. As part of a larger study, two focus groups were conducted for African American MSMs. Participants failed to understand their potential risk for HPV given the higher rates of STD infection experienced by MSMs. They expressed very little knowledge of the HPV vaccine and are also not aware of the complications of HPV virus infection. However, they were very eager to know more about the virus and the vaccine. This study demonstrates the need for the development of health communication intervention and more research targeting African American MSMs and also the need for policy change towards making the HPV vaccine routine for males especially adolescents at no cost.

What is new in HIV infection?

Human immunodeficiency virus (HIV) prevention and treatment updates include screening recommendations, fourth-generation testing, preexposure prophylaxis, and a paradigm shift; treatment is prevention. The U.S. Preventive Services Task Force recommends routine HIV screening in persons 15 to 65 years of age, regardless of risk. Fourth-generation testing is replacing the Western blot and can identify those with acute HIV infection. The U.S. Food and Drug Administration approved the OraQuick In-Home HIV Test; however, there are concerns about reduced sensitivity, possible misinterpretation of results, potential for less effective counseling, and possible cost barriers. Preexposure prophylaxis (effective in select high-risk adult populations) is the combination of safer sex practices and continuous primary care prevention services, plus combination antiretroviral therapy. Concerns for preexposure prophylaxis include the necessity of strict medication adherence, limited use among high-risk populations, and community misconceptions of appropriate use. Evidence supports combination antiretroviral therapy as prevention for acute HIV infection, thus lowering community viral loads. Evidence has increased supporting combination antiretroviral therapy for treatment at any CD4 cell count. Resistance testing should guide therapy in all patients on entry into care. Within two weeks of diagnosis of most opportunistic infections, combination antiretroviral therapy should be started; patients with tuberculosis and cryptococcal meningitis require special considerations.

USPSTF screening recommendations for breast cancer: the potential impact on the African American community.

African American women are more often diagnosed with breast cancer at ages younger than 50, have lower mammography screening rates, have higher breast cancer mortality rates, and more advanced stage at breast tumor diagnoses, than other women. Early detection through mammography screening is important in decreasing mortality. The revised United States Preventive Services Task Force (USPSTF) breast cancer screening guidelines, however, make no recommendation for routine mammography screening in women aged 40-49 years. Given the well-documented disparities experienced by several underrepresented populations, especially African American women, this recommendation has raised concerns among the public and medical community. The 2009 USPSTF breast cancer screening guidelines should be modified to take into account populations with different profiles that put them at higher risk. This commentary describes the burden of breast cancer among African American women and identifies issues with the current USPSTF guidelines that have the potential to uniquely impact African American women and increase breast cancer disparities. This commentary concludes with recommendations for future directions.

Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999-2006.

BACKGROUND: Most melanoma studies use data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program or individual cancer registries. Small numbers of melanoma cases have limited in-depth analyses for all racial and ethnic groups. OBJECTIVE: We sought to describe racial and ethnic variations in melanoma incidence and survival. METHODS: Incidence for invasive melanoma and 5-year melanoma-specific survival were calculated for whites, blacks, American Indians/Alaskan Natives, Asians/Pacific Islanders (API), and Hispanics using data from 38 population-based cancer registries. RESULTS: Incidence rates of melanoma were significantly higher for females than males among whites and Hispanics under 50 years of age and APIs under 40 years of age. White and black patients were older (median age: 59-63 years) compared with Hispanics, American Indians/Alaskan Natives, and API (median age: 52-56 years). The most common histologic type was acral lentiginous melanoma among blacks and superficial spreading melanoma among all other racial and ethnic groups. Hispanics had the highest incidence rate of acral lentiginous melanoma, significantly higher than whites and API. Nonwhites were more likely to have advanced and thicker melanomas at diagnosis and lower melanoma-specific survival compared with whites. LIMITATIONS: Over 50% of melanoma cases did not have specified histology. The numbers of nonwhite patients were still relatively small despite broad population coverage (67% of United States). CONCLUSIONS: Racial and ethnic differences in age at melanoma diagnosis, anatomic sites, and histologic types suggest variations in etiologic pathways. The high percentages of advanced and thicker melanomas among nonwhites highlight the need to improve melanoma awareness for all race and ethnicity in the United States.

Ultrasound tightening of facial and neck skin: a rater-blinded prospective cohort study.

BACKGROUND: Nonablative skin tightening technologies offer the prospect of reduction of wrinkles and skin sagging with minimal downtime, discomfort, and risk of adverse events. The excellent safety profile is mitigated by the limited efficacy of such procedures. OBJECTIVE: We sought to assess the efficacy of ultrasound skin tightening for brow-lift in the context of a procedure treating the full face and neck. METHODS: This was a rater-blinded, prospective cohort study at a dermatology clinic in an urban academic medical center. Subjects were medicated with topical anesthetic and then treated with an investigational focused intense ultrasound tightening device to the forehead, temples, cheeks, submental region, and side of neck using the following probes: 4 MHz, 4.5-mm focal depth; 7 MHz, 4.5-mm focal depth; and 7 MHz, 3.0-mm focal depth. Standardized photographs of front and side views were obtained at 2, 7, 28, 60, and 90 days; rating scales of pain, adverse events, physical findings, and patient satisfaction were also completed. Primary outcome measure was detection of improvement in paired comparison of pretreatment and posttreatment (day 90) photographs by 3 masked expert physician assessors, cosmetic and laser dermatologists, and plastic surgeons who were not authors. Second primary outcome measure was objective brow elevation as quantitated by a standard procedure using fixed landmarks. Secondary outcomes measure was patient satisfaction as measured by a questionnaire. RESULTS: A total of 36 subjects (34 female) were enrolled, one subject dropped out, and 35 subjects were evaluated. Median age was 44 years (range 32-62). On the first primary outcome measure, 30 of 35 subjects (86%) were judged by the 3 masked experienced clinician raters to show clinically significant brow-lift 90 days after treatment (P = .00001). On the second primary outcome measure, mean value of average change in eyebrow height as assessed by measurement of photographs at 90 days was 1.7 mm. LIMITATIONS: Limitations of this study include the inability to quantitatively measure lower face tightening because of the lack of fixed anatomic landmarks in this area. CONCLUSION: Ultrasound appears to be a safe and effective modality for facial skin tightening. A single ultrasound treatment of the forehead produced on average brow height elevation of slightly less than 2 mm. Most treated individuals responded, commonly with accompanying transitory mild erythema and edema.

Temperature dependence of photochemical fluorescence fading in Skh-1 hairless mouse collagen.

BACKGROUND: Type I mammalian collagens have several photolabile fluorescent moieties that absorb UV rays capable of reaching the dermis. We studied the temperature dependence of fluorescence fading as a marker of photochemical damage. METHODS: Collagen solutions were exposed to radiation from 0 to 240 min from either a UVG-11 hand lamp, total dose=1.173 x 10(3) J/m(2); a UVL-21 hand lamp total dose=2.030 x 10(3) J/m(2); or the fluorometer, at 325+/-5 nm, total dose=0.156 x 10(3) J/m(2). We recorded intensities at excitation/emission wavelengths 270/300, 270/330, 270/360, 270/400, 325/400, and 370/450 nm at T=9.0-59.3 degrees C. RESULTS: Results indicated simultaneous forward and reverse reactions. However, the 270/360 nm fluorophore could be analyzed as a second-order reaction. The Arrhenius curve showed two straight lines intersecting near the denaturation temperature, with helix activation energy E(a) approximately 0 and coil E(a)=7.6+/-0.6 kcal/mol (31.7+/-2.5 kJ/mol). DISCUSSION: Collagen-bound fluorophores are not just passive markers of oxidative stress and age-related damage. Their photolability to wavelengths reaching the dermis may result in pathological conditions, particularly at elevated body temperatures.